Triphenylalkene derivatives and their use as selective estrogen receptor modulators

ABSTRACT

The invention provides novel selective estrogen receptor modulator compounds of the general formula:                    
     wherein R1 and R2, which are the same or different are 
     a) H, halogen, OCH 3 , OH; or                    
      where X is O, NH or S; and n is an integer from 1 to 4; and R4 and R5, which are the same or different, are a 1 to 4 carbon alkyl, H, —CH 2 C≡CH or —CH 2 CH 2 OH; or R4 and R5 form an N-containing five- or six-membered ring or heteroaromatic ring; or 
     c) —Y—(CH 2 ) n CH 2 —O—R6 
     where Y is O, NH or S and n is an integer from 1 to 4; and R6 is H, —CH 2 CH 2 OH, or —CH 2 CH 2 Cl; or 
     d) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or carboxymethoxy; and 
     R3 is H, halogen, OH or —OCH 3 ; 
     stereoisomers thereof and their non-toxic pharmaceutically acceptable salts and esters and mixtures thereof, which compounds exhibit valuable pharmacological properties.

This application claims the benefit of Ser. No. 60/165,828 filed Nov.16, 1999.

FIELD OF INVENTION

This invention relates to triphenylalkene derivatives and their use asselective estrogen receptor modulators (SERMs).

BACKGROUND OF INVENTION

The publications and other materials used herein to illuminate thebackground of the invention, and in particular, cases to provideadditional details respecting the practice are incorporated byreference.

Estrogens have been known as female sex hormones. However, lately manytissue-specific properties for estrogens have been described in organs,which are not classically considered to be estrogen-sensitive orestrogen-responsive. During the menopause the secretion of estrogens isdramatically decreased. Subsequently elderly women develop commonlyclimacteric symptoms including hot flushes, sweating, insomnia,depression, headache, vaginal dryness, cardiovascular symptoms, urinaryincontinence, swelling feeling, breast tenderness and fatigue. Inlong-term estrogen deficiency induces cardiovascular disorders andosteoporosis which increase the risk of bone fractures andhospitalizations, which are very expensive to the society. Estrogens areincreasingly used for the treatment of climacteric symptoms, but on theother hand estrogen use increases the risk of uterine and breast cancers(Lobo, 1995). Estrogens are shown to be beneficial also in theprevention of Alzheimer's disease (Henderson, 1997) and in the loweringof LDL-cholesterol values and thus preventing cardiovascular diseases(Grodstein & Stampfer, 1998). New therapies which would have thebenefits of estrogens, but not the carcinogenic risks are requested.Selective estrogen receptor modulators (SERMs) have been developed tofulfill these requirements (Macgregor & Jordan, 1998). However, thepresently used SERMs have properties which are far from optimal. E.g.raloxifen use is limited by its strong antiestrogenic properties, whichcause and worsen the climacteric symptoms, although the effects on thebone are beneficial (Khovidhunkit & Shoback, 1999). It would be mostdesirable to develop tissue-specific estrogens, which could be used inwomen in the treatment of climacteric symptoms, osteoporosis,Alzheimer's disease and/or cardiovascular diseases without thecarcinogenic risk. At the best new SERMs could be given to men toprotect against osteoporosis, cardiovascular diseases and Alzheimer'sdisease without estrogenic adverse events (gynecomastia, decreasedlibido etc.).

OBJECT AND SUMMARY OF THE INVENTION

One object of the present invention is to provide novel selectiveestrogen receptor modulators.

Another object of the present invention is to provide a pharmaceuticalcomposition comprising an amount effective to produce a tissue specificestrogenic and/or antiestrogenic effect of said novel selective estrogenreceptor modulator compound, or a stereoisomer, or a non-toxicpharmaceutically acceptable salt or ester thereof, and apharmaceutically compatible acceptable carrier therefor.

An additional object of the present invention is to provide a method ofproducing a tissue specific estrogenic and/or antiestrogenic effect in asubject in which such an effect is desired which comprises administeringto said subject said novel selective estrogen receptor modulatorcompound, or a stereoisomer, or a non toxic pharmaceutically acceptablesalt or ester thereof in an amount sufficient to produce the desiredeffect.

Thus, according to one aspect this invention concerns novel selectiveestrogen receptor modulator compounds of the general formula:

wherein R1 and R2, which are the same or different are

a) H, halogen, OCH₃, OH; or

where X is O, NH or S; and n is an integer from 1 to 4; and

R4 and R5, which are the same or different, are a 1 to 4 carbon alkyl,H, —CH₂C≡CH or —CH₂CH₂OH; or

R4 and R5 form an N-containing five- or six-membered ring orheteroaromatic ring; or

c) —Y—(CH₂)_(n)CH₂—O—R6

where Y is O, NH or S and n is an integer from 1 to 4; and

R6 is H, —CH₂CH₂OH, or —CH₂CH₂Cl; or

d) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy,1-ethyl-2-hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or carboxymethoxy;and

R3 is H, halogen, OH or —OCH₃;

stereoisomers thereof and non-toxic pharmaceutically acceptable saltsand esters and mixtures thereof, provided that

in the 4-position of the phenyl

where R4 and R5

i) are the same, either methyl or ethyl; or

ii) form an N-containing five-membered ring;

then R1 and R3 cannot simultaneously be H; and

 in the 4-position of the phenyl

where R4 and R5, which are the same or different, are methyl or H; or

when R2 is —O—CH₂CH₂—OH or —O—CH₂COOH in the 4-position of the phenyl,then R1 and R3, cannot simultaneously be H, or OH in the 4-position ofthe phenyl; and

if R1 is OH in the 4-position of the phenyl, R3 cannot be H.

According to another aspect the invention concerns a pharmaceuticalcomposition comprising an amount effective to produce a tissue specificestrogenic and/or antiestrogenic effect of said novel selective estrogenreceptor modulator compound, or a stereoisomer thereof, or a non-toxicpharmaceutically acceptable salt or ester thereof, and apharmaceutically compatible acceptable carrier therefor.

According to an additional aspect the invention concerns a method ofproducing a tissue specific estrogenic and/or antiestrogenic effect in asubject in which such an effect is desired which comprises administeringto said subject said novel selective estrogen receptor modulatorcompound, or a stereoisomer thereof, or a non-toxic pharmaceuticallyacceptable salt or ester thereof in an amount sufficient to produce thedesired effect.

Additional embodiments and advantages of the invention will be set forthin part in the description as follows, and in part will be obvious fromthe description, or may be learned by practice of the invention. Theembodiments and advantages of the invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to the use of novel selective estrogen receptormodulators (SERMs) and their pharmaceutical preparations in men andwomen for the treatment of degenerative diseases and symptoms due toestrogen deficiency. Typically SERMs act as estrogens in bone andcardiovascular system while they are antiestrogenic in breast tissue.SERMs may have agonistic and antagonistic effects in other tissues also.Depending on their chemical structure and hormonal properties somecompounds can be especially suited for elderly women for the preventionof osteoporosis whereas others (which are not feminizing estrogens) mayalso be used in men in the prevention of osteoporosis, cardiovasculardiseases and Alzheimer's disease. Some compounds are specifically suitedfor the treatment of climacteric symptoms in menopausal women. It is thecommon property of the described novel compounds that they areantiestrogenic in the mammary gland and inhibit the proliferation ofbreast cancer cells. They are also weak estrogens in the uterus and donot induce uterine cancers, the side effect of the well known SERM,tamoxifen.

The new SERMs of the present invention thus have tissue-specificestrogenic and/or antiestrogenic effects in vitro and in vivo and areuseful in the prevention and treatment of osteoporosis, cardiovasculardiseases and Alzheimer's disease in men and women, as well as in thetreatment of climacteric symptoms and breast cancer in women.

The compounds of formula (I) can be prepared by a process whichcomprises reaction of a compound of the formula

where R7 is the same as R1 or R2 as defined before or is a protectedsuch group, R₃′ is R3 as defined before or a protected OH, R8 is benzylor tetrahydropyranyl, with an organometallic compound of the formula

where R9 is H , R1 or R2 as defined before or is a protected such groupand M is —Mg-halogen or Li, to give a compound of the formula

where R₃′, R7, R8, and R9 are as defined above. R8 is tetrahydropyranylwhen R7 or R9 is —X—(CH₂)_(n)CH₂—OR6 where X and n are as defined in(I). The compound (IV) is dehydrated by an appropriate acid catalystpreferable with acetic anhydride/acetyl chloride to give atriphenylethylene derivative of the formula

where R₈′ is H or benzyl, R₇′ and R₉′ are R1 and R2 or benzyl protectedOH or benzyl protected —XCH₂CH₂OR6. The possible protectingtetrahydropyranyl groups in R3, R7, R8 and R9 are removed in thisprocess to give radicals R3, R₇′, R₈′ and R₉′.

The removal of the possible benzylic R₈′ can be carried out by treatmentwith Zn and acetyl chloride in toluene to give the triphenylbutenol ofthe formula

The hydroxy compound (VI) can be converted to a corresponding chlorideby treatment with thionyl chloride or with triphenyl phosphine-carbontetrachloride in organic solvent to give the compound of the formula

The claimed compounds (I) are prepared from the compounds of the formula(VII) where R₇′ and/or R₉′ are benzyl protected —XCH₂CH₂OR6 by treatmentwith Zn and acetyl chloride in organic solvent or by catalytichydrogenation.

Another process to prepare compounds of the formula (IV) is thehydroalumination reaction of a “styrene” derivative of the formula

where R10 is —CHO, —CH₂OH, —COOH or a corresponding ester and R3 is asdefined before with a benzophenone derivative of the formula

Yet another process for the preparation of the compounds of theinvention comprises O-alkylation of the compound of the formula (V)where R₇′, and/or R₉′ is OH with an alkyl halide derivative of theformula

R11-(CH₂)_(m)-halogen  (X)

where m is an integer from 1 to 5 and R11 is halogen,

where R₆′ is R6 or protected R6, or —COOR to give a compound of theformula

The compound of the formula (XI) where R11 is halogen is reacted with anamine of the formula

to give a compound of the formula

Yet another process for the preparation of the compounds of the formula(VII) comprises the McMurry reaction of an benzophenone derivative ofthe formula

where R₇′ and R₉′ are as defined before, with an 3-chloropropiophenonederivative of the formula

where R3 is as defined before.

The claimed compound of the formula (I) where R1 or R2 is2,2-diethyl-2-hydroxyethoxy can be prepared by reaction of the compoundof the formula (XI), where m is 1 and R11 is —COOR, with ethylmagnesiumbromide.

The claimed compound of the formula (I) where R1 or R2 is1-ethyl-2-hydroxyethoxy can be prepared by O-alkylation of the compoundof the formula (V), where R₇′ or R₉′ is OH with ethyl α-bromobutyrateand by reduction of the formed ester by lithium aluminum hydride.

Compounds of formula (I) contain one or more asymmetric centers and maythus give rise to enantiomers, diastereomers and other stereoisomericforms. The present invention is also meant to encompass racemicmixtures, resolved forms and mixtures thereof as well as the individualenantiomers that may be separated according to methods known to those ofordinary skill in the art.

The invention disclosed herein is also meant to encompass non-toxicpharmaceutically acceptable salts and esters of compounds of formula (I)and their stereoisomers. The non-toxic pharmaceutically acceptable saltsand esters can be prepared by methods well-known to those of ordinaryskill in the art. The non-toxic pharmaceutically acceptable saltsinclude, but are not limited to, chlorides, bromides, sulfates,nitrates, phosphates, sulfonates, formates, tartrates, maleates,citrates, benzoates, salicylates, ascorbates and the like. The non-toxicpharmaceutically esters include, but are not limited to, methyl esters,ethyl esters, propyl esters, butyl esters and the like.

EXPERIMENTAL SECTION Methods

Evaluation of Estrogenic and Antiestrogenic Properties of Compounds inMCF-7 Cell Growth Experiments In Vitro

Estrogen-sensitive human breast cancer cells, MCF-7 (McGrath clone),were maintained in RPMI-1640 medium supplemented with 10% fetal calfserum, 2 mM L-glutamine, 10 μg/ml insulin and 10 μg/ml gentamicin. Thecells were grown as monolayer cultures in 75 cm² plastic tissue cultureflask (Nunc, Roskilde, Denmark) in 25 ml medium at 37° C. in anatmosphere of 95% air, 5% CO₂ and subcultured twice a week.

For experiments involving hormone or anti-hormone treatment, the cellsin exponential growth phase were precultivated in the absence ofestradiol for one day. Cells were plated at a density of 3.5×10³cells/well in 96-well microtiter plates (Nunclon, Roskilde, Denmark) andincubated for 24 hours at 37° C., 95% air, 5% CO₂, RPMI-1640 medium(L-glutamine and gentamicin as above) with 5% stripped fetal calf serum(stripped twice with dextran-coated charcoal to remove the steroids) andwithout phenol red. After the incubation period the medium was removed.The exposure to study drugs was started immediately by adding freshmedium with 5% stripped serum. Half of the cells were grown withestradiol, half without estradiol. Study compounds (dissolved in ethanolin 0.01 M concentration and diluted with the growth medium asappropriate) were added. The final concentrations of the compounds were1, 10, and 100 nM, and 1 and 10 μM. The cells were incubated for fourdays.

The amount of living cells was measured after 4 days by luminometerbased on the amount of ATP and luciferase reaction as described byKangas et al, 1984. This method allows evaluation of estrogenicity basedon the ability of the compounds to stimulate the growth of theestrogen-dependent cells in the absence of estradiol. Estrogenicity wasestimated by comparing the maximal growth stimulus (at anyconcentration) of study compound as per cent from growth stimulus byestradiol (100% stimulus). In the present studies antagonism wasestimated at the concentration of 1 μmol/l as per cent of theoreticalfull (100%) antagonism, which would mean complete inhibition ofestradiol-stimulus. At high concentrations molecules may also showtoxicity. Toxicity was estimated as the fraction of dead cells (i.e.100% means that all cells have died during the exposure). The resultsare presented in Table 2.

Estimation of Estrogenicity and Antiestrogenicity In Vivo

The classical method to evaluate estrogenic and antiestrogenic effect isimmature mouse or rat uterus (Terenius, 1971). The animals were exposedfor 3 days to the compounds to be investigated at the age of 18 days. Onthe fourth day the animals were asphyxicated with CO₂ and body weightand uterine weight was recorded. Estrogens increase the size and weightof the uterus (uterotropic effect) while antiestrogens inhibit thisaction. The compounds are therefore given alone and with estradiol inorder to evaluate both agonistic and antagonistic effects. The resultshave been shown in Table 3 both as per cent of estrogen stimulation(100%), and as inhibition of estrogen action (full inhibition is 100%).The values are given at two dose levels, low i.e. 3-5 mg/kg and highi.e. 10-50 mg/kg. Estrogenic activity can be estimated also after a 4weeks' treatment of ovariectomized rats based on the uterine size. Thisassay was carried out in selected molecules as shown in Table 4.

Estimation of Effects to Cholesterol and Bone

Compounds were given p.o. to female rats for 4 or 5 weeks daily. At theend a blood sample was taken. Serum was separated by centrifugation andfrozen until analyzed for total amount of cholesterol. Bone samples weretaken from vertebra and tibia. Physical strength of the bones wasstudied as described by Peng et al, 1994. The assessments of the boneincluded:

Ash Weight of Tibial Epiphyses

Epiphyses of one tibia was carefully prepared and burned. Samples wereburned to remove water and organic material. Ash weight relates to themineral content of the bone. In addition, bone samples were taken tostudy the histomorphometry. In some cases the bone formation was studiedby injecting tetracycline (50 mg/kg i.p. 10 days before autopsy) andcalcein (20 mg/kg i.p. 3 days before autopsy). The method is based onpermanent binding of tetracycline into growing bone and its detection byfluorescence (Peng et al, 1994).

Mechanical Testing of Bones

The mechanical testing of bones was carried out by materials testingmachine, constructed in-house at Oulu University (Technical ServicesDepartment of the Medical Faculty). The testing machine is based onlever arm principle. One end of a steel lever is fixed. The pressing rodand the driving motor are connected to the lever arm with a moment ratioof 12.5 cm/50 cm=¼. As a driving motor a linear actuator (SEY 10Magnetic Elektromotoren AG, Switzerland) is used to obtain constantvertical movement (0.62 cm/s). The interchangeable compression head ismounted on the pressing rod for different tests transmitting compressiveforce to the specimen, and moving at a constant speed of 0.155 mm/s upto a maximal load capacity of 1200 N. The pressing rod is guided via anaxial ball bearing to keep the movement vertical. Compressive force ismeasured by a temperature-compensated force sensor, which is attached tothe stationary part of the compression stage. The measuring electronicsinclude sensor calibration and adjustments.

Strength of Femoral Neck

The maximal load on the femoral neck was measured by the cantileverbending test. The supporter for the bone was a thick polymethylmethacrylate plate in which several holes of different sizes weredrilled. On one side of each hole a groove was engraved for the thirdtrochanter of the femur. The femur was cut exactly between the middleand lower third of the shaft. The bone was inserted perpendicularly andtightly into a suitable hole on the supporter. The lesser trochanter ofeach bone touched the surface of the plate. This procedure allowed rapidand stable fixation of the bone without using any additional embeddingmaterials. The concave compressing head, 2.5 mm in diameter, was made ofaluminum. The femoral head-neck complex was tested until failure byloading the head with a force parallel to the shaft.

Estimation of Antitumor Activity In Vivo

Antitumor activity was estimated by using DMBA(dimethylbenz[a]anthracene) model. One single peroral dose of DMBA (12mg) initiates mammary gland carcinogenesis. New compounds wereadministered for 5 weeks when palpable tumors appeared. Size of thetumors and number of new tumors were carefully estimated once a weekuntil termination. The model has been described in detail by Kangas etal, 1986. The growth of the tumors was measured once a week. All tumorswere classified according to their growth properties to progressing,stable and regressing ones. Disappeared tumors were separatelycalculated. The tumors were considered to be progressing, if the tumorvolume grew more than 8-fold during the 5 weeks dosing period, andregressing if the tumor volume decreased to one fourth or less from thevolume in the beginning. If tumor volume changed less or remainedunchanged, the tumors were considered to be stable.

Results

Altogether 46 compounds were evaluated by the methods described abovewhich are included in the list of example compounds numbered and listedin Table 1.

TABLE 1 Reference numbers (No.) and names of example compounds. No.Compound 1 (E)-(2-{4-[4-Chloro-1-(4-fluorophenyl)-2-phenylbut-1-enyl]phenoxy}ethyl)-dimethylamine 2(Z)-(2-{4-[4-Chloro-1-(4-fluorophenyl)-2-phenylbut-1-enyl]phenoxy}ethyl)-dimethylamine 3(E)-(2-{4-[4-Chloro-1-(4-chlorophenyl)-2-phenylbut-1-enyl]phenoxy}ethyl)-dimethylamine 4(E)-(2-{4-[4-Chloro-1,2-bis(4-chlorophenyl)but-1-enyl]phenoxy}ethyl)-dimethylamine 5(Z)-(2-{4-[4-Chloro-1,2-bis(4-chlorophenyl)but-1-enyl]phenoxy}ethyl)-dimethylamine 6(E)-4-Chloro-1-[4-(2-chloroethoxy)phenyl]-1,2-bis(4-chlorophenyl)-but-1-ene 7(Z)-4-Chloro-1-[4-(2-chloroethoxy)phenyl]-1,2-bis(4-chlorophenyl)-but-1-ene 8 (E)-2-{4-[4-Chloro-2-phenyl-1-(4-fluorophenyl)but-1-enyl]phenoxy}ethanol 9 (E)-2-{4-[4-Chloro-1,2-bis(4-chlorophenyl)but-1-enyl]phenoxy}ethanol 10(E)-3-{4-[4-Chloro-1-(4-chlorophenyl)-2-phenyl-but-1-enyl]phenoxy}-propane-1,2-diol 11(Z)-4-Chloro-1-[4-(2-methylsulfanyl-ethoxy)phenyl]-1,2-diphenyl-but-1-ene 12 (E)-{4-[4-Chloro-1-(4-chlorophenyl)-2-phenylbut-1-enyl]phenoxy}acetic acid 13(Z)-{4-[4-Chloro-1-(4-chlorophenyl)-2-phenylbut-1-enyl] phenoxy}aceticacid 14 (E)-1-(4-{2-[(2-Chloroethoxy]ethoxy}phenyl)-4-chloro-1-(4-chloro-phenyl)-2-phenyl-but-1-ene 15(E)-1-(4-{2-[(2-Chloroethoxy]ethoxy}phenyl)-4-chloro-1-(4-fluorophenyl)-2-phenyl-but-1-ene 16 2-(4-{4-Chloro-1-[4-(2-hydroxyethoxy)phenyl]-2-phenyl- but-1-enyl}phenoxy)-1-ethanol 17(E)-2-{4-[4-Chloro-2-phenyl-1-(4-chlorophenyl)but-1-enyl]phenoxy}ethanol 18(Z)-2-[3-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol 19(Z)-2-{2-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy] ethoxy}ethanol 20(Z)-3-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy] propane-1,2-diol 21(Z)-1-{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethyl}-1H-imidazole 22 (Z)-2-({2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethyl}methylamino)ethanol 23(Z)-(2-{4-[4-Chloro-2-(4-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}ethyl)-dimethylamine 24(E)-(2-{4-[4-Chloro-2-(4-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}ethyl)-dimethylamine 25(Z)-(2-{4-[4-Chloro-2-(4-fluorophenyl)-1-phenylbut-1-enyl]phenoxy}ethyl)-dimethylamine 26(Z)-(2-{4-[4-Chloro-2-(4-chlorophenyl)-1-(4-methoxyphenyl)but-1-enyl]phenoxy}-ethyl)dimethylamine 27(E)-(2-{4-[4-Chloro-2-(4-chlorophenyl)-1-(4-methoxyphenyl)but-1-enyl]phenoxy}-ethyl)dimethylamine 28(Z)-1-(2-{4-[4-Chloro-2-(3-methoxyphenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl)piperidine 29(E)-1-(2-{4-[4-Chloro-2-(3-methoxyphenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl)piperidine 30(Z)-1-(2-{4-[4-Chloro-2-(2-methoxyphenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl)piperidine 31(E)-1-(2-{4-[4-Chloro-2-(2-methoxyphenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl)piperidine 32(Z)-1-(4-(2-Dimethylaminoethylsulfanyl)phenyl]-1,2-diphenyl-4-chloro-but-1-ene 33(Z)-{2-[3-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]ethyl} dimethylamine34 (E)-3-{4-Chloro-1-[4-(2-hydroxyethoxy)phenyl]-2-phenyl-but-1-enyl}-phenol 35(Z)-3-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]propan-1-ol 36(Z)-2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenylsulfanyl]ethanol 37(Z)-2-{4-[4-Chloro-2-(4-chlorophenyl)-1-(4-methoxyphenyl)but-1-enyl]-phenoxy}ethanol 38(Z)-1-(2-{4-[4-Chloro-2-(2-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}-ethyl)piperidine 39(E)-3-{4-Chloro-1-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenyl-but-1-enyl}-phenol 40(Z)-3-{4-Chloro-1-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenyl-but-1-enyl}-phenol 41(Z)-2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenylamino]ethanol 42(Z)-4-{1-(2-Chloroethyl)-2-[4-(2-hydroxyethoxy)phenyl]-2-phenylvinyl}phenol 43(E)-4-{1-(2-Chloroethyl)-2-[4-(2-hydroxyethoxy)phenyl]-2-phenylvinyl}phenol 44(Z)-{2-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]ethyl}-methylprop-2-ynylamine 45(Z)-3-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxymethyl] pentan-3-ol 46(Z)-2-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]butan-l-ol 47N-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenyl]-N′,N′-dimethylethane-1,2-diamine

The structures of the example compounds are summarized as follows:

Compounds with a dimethylaminoethoxy tail

R1 R3 No. 4-F H 1 and 2 4-Cl H 3 4-Cl 4-Cl 4 and 5 H 4-Cl 23 and 24 H4-F 25 4-OCH₃ 4-Cl 26 and 27

No. 32

No. 33

No. 47 Compounds with a dimethylaminoethoxy tail

R1 R3 R No. H H CH₂CH₂imidazolyl 21 H H CH₂CH₂N(CH₃)CH₂CH₂OH 22 H 3-OCH₃CH₂CH₂piperidinyl 28 and 29 H 4-OCH₃ CH₂CH₂piperidinyl 30 and 31 H 2-ClCH₂CH₂piperidinyl 38 3-OH H CH₂CH₂imidazolyl 39 and 40 H HCH₂CH₂N(CH₃)CH₂C≡CH 44 Alcohols

R1 R3 No. 4-F H 8 4-Cl 4-Cl 9 4-OCH₂CH₂OH H 16 4-Cl H 17 3-OH H 344-OCH₃ 4-Cl 37 H 4-OH 42 and 43

No. 18

R1 R3 R No. 4-Cl 4-Cl CH₂CH₂Cl 6 and 7 4-Cl H CH₂CH(OH)CH₂OH 10 H HCH₂CH₂SCH₃ 11 4-Cl H CH₂COOH 12 and 13 4-Cl H CH₂CH₂OCH₂CH₂Cl 14 4-F HCH₂CH₂OCH₂CH₂Cl 15 H H CH₂CH₂OCH₂CH₂OH 19 H H CH₂CH(OH)CH₂OH 20 H HCH₂CH₂CH₂OH 35 H H CHC(OH)(CH₂CH₃)₂ 45 H H CH(CH₂CH₃)CH₂OH 46

No. 36

No. 41

The estrogenic and antiestrogenic as well as cytotoxic effects ofseveral compounds in vitro are presented in Table 2. It can be seen thatthe spectrum of hormonal activity of the compounds varies and thus givesthe possibility to use the compounds in different clinical conditions.

Compounds with weak hormonal activity, which kill MCF-7 cells (humanbreast cancer cells) effectively at the highest investigatedconcentration (10 μM) could be used preferably in the treatment ofbreast cancer. Such compounds are among others compounds No. 1, 3, 16,19, 26, 27, 39 and 40 (Table 2). These compounds and several others areless effective estrogens and antiestrogens than the well known breastcancer drugs tamoxifen and toremifene (Table 3). Especially compound No.19 is of interest, because it is a more effective anticancer drug invivo in the DMBA-induced rat mammary tumor model even at very low dosesthan clinically used tamoxifen and toremifene (Table 6).

Compounds with weak estrogenic and no antiestrogenic action could beespecially suitable for the prevention and treatment of osteoporosis andclimacteric symptoms. Such compounds are (among others) compounds No. 3,10, 11, 18, 19, 20, 25, 32, 36 and 44 (Tables 2, 3 and 4).

Compounds, which decrease cholesterol could be useful as cardiovasculardrugs. For women some estrogenicity for such compounds can be allowed,but compounds which are not estrogens or are very weak estrogens anddecrease cholesterol, could be used also in men for the prevention andtreatment of cardiovascular diseases. Such compounds include (amongothers) compounds No. 3, 19, 20 (also for men) and 33 (for women) (Table4). The same compounds are expected to be useful also in the treatmentor prevention of Alzheimer's disease. In the latter case the cytotoxicaction of the compounds should be weak, like e.g. with compound No. 33(Table 2). It should be noted that compound No. 19 does not show anyestrogenic action on the weight of the prostate gland at doses which areactive in DMBA-induced mammary tumor model (Tables 6 and 7). Thereforeit could be of special benefit in men and could be of benefit inaddition to the above mentioned conditions in the treatment of prostatecancer.

The hormonal profile of the compounds may be in some cases different invitro and in vivo, e.g. compound No. 1 has no estrogenic action in vitro(Table 2), but is a weak estrogen in vivo (Table 3). Therefore theexamples above should be understood as examples of the usefulness indifferent conditions. They should not be understood as limitations fortheir possible use in different clinical indications.

TABLE 2 Estrogenic, antiestrogenic, and cytotoxic effects of studycompounds in MCF-7 cells. The details of estimations are given in thetext. Maximal estrogenic agonism in the absence of estradiol wascalculated in per cent of estradiol-stimulus (100%). Antiestrogenicproperty was evaluated at the concentration of 1 μmol/l consideringtheoretical full antagonism as 100 per cent. Toxicity at theconcentration of 10 μmol/l was evaluated as a fraction of dead cellswhen compared to the control (i.e. 100 means that all cells are dead).Known antiestrogens were used as references. Without estradiol (E2) Withestradiol (E2) Maximal Antagonism Maximal Maximal Cell Kill at 1 μM CellKill Compound Agonism (% fraction (% of full (% fraction No. (% of E2)of dead cells) antagonism) of dead cells)  1 1 100 8 100  2 100 32 29100  3 1 100 1 94  4 10 90 10 100  5 11 100 31 100  6 0 47 16 40  8 31 292 52  9 14 45 9 62 10 34 7 0 35 11 14 26 0 55 14 12 10 27 57 15 74 82 59 16 22 90 23 96 17 0 44 17 38 18 30 10 1 40 19 14 14 21 50 20 8 5 25 6021 5 80 0 91 22 1 15 12 41 23 14 89 5 93 24 46 89 4 98 25 17 42 6 27 260 97 11 98 27 0 99 5 100 28 3 86 18 92 30 5 91 4 92 32 11 86 0 90 33 200 58 80 34 0 0 0 0 35 45 50 14 50 36 8 17 13 37 37 4 39 0 41 38 0 99 68100 39 0 68 17 78 40 0 63 3 46 41 54 0 10 47 42 9 23 13 54 43 78 80 6 2244 24 78 8 95 45 15 6 3 19 46 18 15 23 51 Tamoxifen 31 100 43 100Toremifene 37 100 44 100 FC-1271a 23 50 21 80 ICI 164,384 9 100 100 100

TABLE 3 Uterotropic (e.g. estrogenic) and estrogen antagonistic effectof study compounds in the 3 day uterotropic assay in immature femalerats. Estrogenic effect is estimated as per cent of maximal,estrogen-induced, action. Antiestrogenic effect is presented as per centof theoretical complete inhibition of estrogen action (100%).Uterotropic effect Estrogen antagonism Compound (% of estradiol) (%inhibition of estradiol) No. Given without estradiol Given withestradiol dose: 3-5 mg/kg 10-50 mg/kg 3-5 mg/kg 10-50 mg/kg  1 42 74 2631  3 44 54 65 38 19 13 37 10 44 20 33 62  5 20 20 48 72 26 39 21 26 3910 20 35 43 66 35 32 36 14 29  0  5 38 73 72  0 12 39  9 19 50 70 40 13 9 45 54 44 55 75 n.d. 42 45 43 62 30 30 46 77 100   0  0 Tamoxifen 4451 51 58 Toremifen 26 44 45 58 Raloxifene 11 13 90 92 Size of the uterusafter a 4 weeks treatment of ovariectomized rats with the new compounds(peroral daily doses indicated in mg/kg). Sham-operated, estradioltreated and raloxifene treated ovariectomized rats served as controls.Group Uterine size (g) Sham control 0.497 ± 0.103 Ovariectomized 0.099 ±0.016 No. 3 3.0 mg/kg 0.140 ± 0.006 No. 19 1.0 mg/kg 0.192 ± 0.029 No.19 5.0 mg/kg 0.221 ± 0.023 No. 20 1.0 mg/kg 0.133 ± 0.032 Raloxifene 3.0mg/kg 0.141 ± 0.021 FC-1271a 5 mg/kg 0.411 ± 0.042

TABLE 4 Effect of compound No. 3, 19 and 20 on rat serum cholesterollevel in ovariectomized (OVX) rats after 4 weeks dosing. Estradiol wasgiven to one group for comparison. The result indicates that ovariectomycauses increase of cholesterol level. Estradiol, compound No. 3, 19 and20 can prevent this increase even at very low dose and decrease thelevel below the sham operated level. Number of animals was 8 in eachgroup. Group Cholesterol level (mmol/l) in serum Sham operated rat 3.8 ±0.4 OVX rat 4.6 ± 0.7 OVX rat + 4.0 ± 0.4 estradiol 3 μg/kg OVX + No. 33 mg/kg 3.1 ± 0.4 OVX + No. 19 0.3 mg/kg 3.6 ± 0.4 OVX + No. 19 10 mg/kg3.9 ± 0.6 OVX + No. 20 1 mg/kg 3.3 ± 0.6 OVX + No. 20 5 mg/kg 2.3 ± 0.4

TABLE 5 Effect of compounds No. 3, 19 and 20 on bone in ovariectomizedrats after 4 weeks dosing. Rats were ovariectomized (controls shamoperated). Compounds were given for 4 weeks at indicated doses (mg/kg)p.o. beginning one week after the ovariectomy. Tibial epiphyses andfemoral neck were prepared for the estimation of the quality of thebone. Ash weight (mg) Maximal load (N) Group and dose (mg/kg) of tibialepiphyses of femoral neck Sham control (n = 10) 34.0 ± 2.9 86.7 ± 10.4*OVX (n = 10) 32.2 ± 2.8 68.4 ± 8.5 No. 3 3.0 mg/kg (n = 22) 36.0 ± 3.4*92.5 ± 11.1* No. 19 1.0 mg/kg (n = 10) 34.8 ± 1.3* 81.6 ± 7.9* No. 195.0 mg/kg (n = 10) 34.9 ± 1.9* 85.7 ± 17.0* No. 20 3.0 mg/kg (n = 20)35.0 ± 3.2 81.7 ± 15.2* Raloxifene 3.0 mg/kg (n = 10) 34.9 ± 3.5 84.2 ±18.4* *indicates statistically significant (p < 0.05) difference toovariectomized animals

TABLE 6 Antitumor effect of compound No. 19 on DMBA-induced rat mammarygland cancer. Compound No. 19 was given p.o. daily for 5 weeks at theindicated doses. Tumors were classified to growing, stable, regressingand disappeared as described in the text. Number of tumors in each groupwas counted and calculated as per cent of total tumor number. Number ofanimals in each group was 7. Compound No. 19 did not influence on thebody weight of the animals when compared to controls. Grow- Group ingStable Regressing Disappeared Control 82% 18%  0%  0% No. 19  3 mg/kg20% 20% 40% 20% No. 19 15 mg/kg 14% 14% 57% 14% Tamoxifene  3 mg/kg 36%56%  8%  0% Toremifene  3 mg/kg 31% 51% 11% 10%

TABLE 7 Effect of compound No. 19 on the weight of the prostate gland inintact and castrated male rats after 4 weeks daily treatment with twodifferent doses. Castration decreases markedly the prostate weight andestrogens are known to do the same. Compound No. 19 has no estrogeniceffect at the dose of 0.5 mg/kg and is weakly estrogenic at the dose of5.0 mg/kg. Note that this compound has significant antitumor action inthe DMBA-induced mammary cancer model at 0.5 mg/kg dosage (Table 6).Weight of the prostate gland Group (mg) mean and sd Control 2.60 ± 0.77Castrated rats 0.59 ± 0.07 No. 19 0.5 mg/kg 2.66 ± 0.21 No. 19 5.0 mg/kg1.58 ± 0.50 No. 19 0.5 mg/kg to castrated rats 0.59 ± 0.07 No. 19 5.0mg/kg to castrated rats 0.62 ± 0.07

For the purpose of this invention, the novel SERMs, their stereoisomersor pharmaceutically acceptable salts thereof can be administered byvarious routes. The suitable administration forms include, for example,oral formulations, parenteral injections including intravenous,intramuscular, intradermal and subcutaneous injections; and transdermalor rectal formulations. Suitable oral formulations include e.g.conventional or slow-release tablets and gelatin capsules.

The required dosing of the novel SERMs will vary with the particularcondition being treated, the severity of the condition, the duration ofthe treatment, administration route and specific compounds beingemployed. Typically the daily dose for an adult person is 5-200 mg,preferably 20-100 mg. SERMs can be given as tablets or otherformulations like gelatin capsules alone or mixed in any clinicallyacceptable non-active ingredients which are used in the pharmaceuticalindustry.

EXAMPLES Example 1 a) O-alkylation of 4-Hydroxybenzophenone Derivatives

In Phase Transfer Catalysis (PTC) Conditions

[4-(2-Dimethylaminoethoxy)phenyl]-(4-fluorophenyl)methanone

4-Hydroxybenzophenone (28.1 g, 0.13 mol) is dissolved in toluene (140ml). Tetrabutylammonium bromide (TBABr) (2.1 g) is added. Aqueous 48%sodium hydroxide (140 ml) is added at 50-55° C. The mixture is heated to80° C. and 2-chloroethyldimethylamine hydrochloride (total 20.0 g, 0.14mol) is added in small portions and the reaction mixture is stirred at97-100° C. for 3 h. The layers are separated and the organic layer iswashed with water, dried over sodium sulfate and evaporated to dryness.Yield 33.0 g, 88%. The product is used for the next step without furtherpurification.

¹H NMR (CDCl₃): 2.36 (s, 6H), 2.77 (t, 2H), 4.15 (t, 2H), 6.99 (d, 2H),7.15 (t, 2H), 7.27-7.83 (m, 4H).

Using the same method the following compounds are prepared:

(4-Clorophenyl)-[4-(2-dimethylaminoethoxy)phenyl]methanone

¹H NMR (CDCl₃): 2.36 (s, 6H), 2.77 (t, 2H), 4.15 (t, 2H), 6.98 (d, 2H),7.45 (2H), 7.71 (d, 2H), 7.79 (d, 2H).

[4-(2-Benzyloxyethoxy)phenyl]-(4-fluorophenyl)methanone

¹H NMR (CDCl₃): 3.87 (dist.t, 2H), 4.24 (dist.t, 2H), 4.65 (s, 2H), 6.99(d, 2H), 7.15 (t, 2H), 7.32-7.39 (m, 5H), 7.76-7.83 (m, 4H).

[4-(2-Benzyloxyethoxy)phenyl]-(4-chlorophenyl)methanone

¹H NMR (CDCl₃): 3.86 (t, 2H), 4.24 (t, 2H), 4.65 (s, 2H), 6.99 (d, 2H),7.3-7.4 (m, 5H), 7.45 (d, 2H), 7.70 (d, 2H), 7.78 (d, 2H).

By Acid Catalysis

(4-Chlorophenyl)-[4-(tetrahydropyranyloxy)phenyl]methanone

4-Chloro-4′-hydroxybenzophenone (50 g, 0.215 mol) is dissolved indichloromethane (400 ml). 3,4-Dihydro-2H-pyran (21.7 g, 0.257 mol) and acatalytic amount of p-toluenesulfonic acid are added to the solution.The solution is stirred for 6 hours at room temperature and then allowedto stand over night. 1 N aqueous sodium hydroxide solution (100 ml) isadded to the reaction mixture and stirred for 15 minutes. Organic layeris separated and washed twice with 1 N aqueous sodium hydroxide solutionand once with water. Dichloromethane solution is dried and evaporated todryness. Yield 68.6 g.

¹H NMR (CDCl₃): 1.52-2.20 (m, 6H), 3.60-3.67 (m, 1H), 3.8-3.94 (m, 1H),5.5-5.6 (m, 1H), 7.10 (d, 2H), 7.45 (d, 2H), 7.72 (d, 2H), 7.78 (d, 2H).

Using the same method the following compound is prepared:

bis[4-(Tetrahydropyranyloxy)phenyl]methanone

¹H NMR (CDCl₃): 1.55-2.20 (m, 12H), 3.6-3.7 (m, 2H), 3.8-4.0 (m, 2H),5.5-6.6 (m, 2H), 7.11 (d, 4H), 7.78 (d, 4H).

NaH as a Base

(4-Chlorophenyl)-[4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-methanone

Sodium hydride (3.4 g, 0.072 mol) in oil is washed with heptane andmixed with dimethyl formamide (DMF) (120 ml).4-Chloro-4′-hydroxybenzophenone (12 g, 0.052 mol) in DMF is addeddropwise to the solution and the reaction mixture is stirred for an hourat room temperature. Then toluene-4-sulfonic acid2,2-dimethyl-[1,3]dioxolan-4-yl methyl ester (17.7 g, 0.0618 mol,prepared from S-1,2-O-isopropyl glycerol and p-toluenesulfonyl chloride)in DMF is added dropwise to the solution during an hour. The mixture isheated to 60° C. and stirred at that temperature for two days. 1 Naqueous sodium hydroxide solution (200 ml) is added to reaction mixtureand the solution is extracted three times with toluene (60 ml). Toluenelayers are combined and washed twice with water (60 ml), dried andevaporated to dryness. The residue is crystallized from methanol. Yield13.7 g, 76.7%.

¹H NMR (CDCl₃): 1.42 (s, 3H), 1.48 (s, 3H), 3.90-4.24 (m, 4H), 4.52(quintet, 1H), 6.99 (d, 2H), 7.46 (d, 2H), 7.71 (d, 2H), 7.79 (d, 2H).

b) Hydroalumination Reaction of Benzophenone Derivatives WithCinnamaldehyde or a Methyl Cinnamate

1-[4-(2-N,N-Dimethylaminoethoxy)phenyl]-1-(4-fluorophenyl)-2-phenylbutane-1,4-diol

Lithium aluminum hydride (2.6 g, 0.068 mol) is added into drytetrahydrofuran (120 ml) under nitrogen atmosphere. Cinnamaldehyde (13.8g, 0.1 mol) in dry tetrahydrofuran (30 ml) is added at 24-28° C. Thereaction mixture is stirred at ambient temperature for 1 h.[4-(2-Dimethylaminoethoxy)phenyl]-(4-fluorophenyl)methanone (29.6 g,0.103 mol) in dry tetrahydrofuran (60 ml) is added at 50-55° C. Thereaction mixture is stirred at 60° C. for 3 h. Most of tetrahydrofuranis evaporated. Toluene (300 ml), 48% aqueous sodium hydroxide (118 ml)and water (30 ml) are added. The mixture is refluxed for 10 min and theaqueous layer is separated while warm. The NaOH treatment is repeated.The toluene layer is washed twice with hot water. The product iscrystallized from toluene as a mixture of stereoisomers (26.4 g, 62%).

¹H NMR (CDCl₃+MeOH-d₄): 1.95-2.12 (m, 2H), 2.30 and 2.37 (2s, together6H), 2.68 and 2.77 (2t, together 2H), 3.31-3.48 (m, 2H) under which thesignal of CHCH₂ of the other diastereoisomer, 3.80 (dd, CHCH₂ the otherdiastereoisomer), 3.95 and 4.08 (2t, together 2H), 6.62 and 6.91 (2d,together 2H), 7.03 and 6.72 (2t, together 2H), 7.05-7.20 (m, 7H), 7.51(m, 2H).

Using the same method the following compounds are prepared:

1-(4-Chlorophenyl)-1-[4-(2-N,N-dimethylaminoethoxy)phenyl]-2-phenylbutane1 4-diol, mixture of stereoisomers.

¹H NMR (CDCl₃+MeOH-d₄): 1.85-2.10 (m, 2H), 2.27 and 2.33 (2s, together6H), 2.66 and 2.75 (2t, together 2H), 3.25-3.50 (m, 2H), 3.62 and 3.84(t and dd, together 1H), 3.93 and 4.04 (2t, together 2H), 6.6-7.6 (13H).

1-[4-(2-Benzyloxyethoxy)phenyl]-1-(4-fluorophenyl)-2-phenylbutane-1,4-diol,mixture of stereoisomers.

¹H NMR (CDCl₃): 1.92-2.15 (m, 2H), 3.30-3.48 and 3.48-3.66 (2m, together2H), 3.74 and 3.83 (2 dist.t, together 2H), 4.02 and 4.15 (2 dist.t,together 2H), under the two last signal groups CHCH₂, 4.58 and 4.63 (2s,together 2H), 6.6-7.6 (18H).

1-[4-(2-Benzyloxyethoxy)phenyl]-1,2-bis(4-chlorophenyl)butane-1,4-diol,mixture of stereoisomers.

4-Chlorocinnamic acid methyl ester is used instead of cinnamaldehyde.

¹H NMR (CDCl₃): 1.80-2.15 (m, 2H), 3.2-3.4 and 3.4-3.6 (2m, together2H), 3.75 and 3.82 (2 t, together 2H), 3.95 (dist.t, 1H), 4.00 and 4.14(2 t, together 2H), 4.59 and 4.63 (2s, together 2H), 6.80-7.55 (17H).

1,2-Bis(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]butane-1,4-diol,mixture of stereoisomers.

4-Chlorocinnamic acid methyl ester is used instead of cinnamaldehyde.

¹H NMR (CDCl₃+MeOH-d₄): 1.85-2.20 (m, 2H), 2.35 and 2.37 (2s, together6H), 2.77 and 2.82 (2t, together 2H), 3.20-3.45 (m, together 2H), 3.81and 3.85 (2 dist. t, together 1H), 4.10 and 4.21 (2 t, together 2H),6.9-7.8 (m, 12H).

1,1-bis[4-(Tetrahydropyranyloxy)phenyl]-2-phenylbutane-1,4-diol

¹H NMR (CDCl₃): 1.5-2.1 (m, 14H), 3.3-4.1 (m, 7H), 5.25-5.28 (m, 1H),6.77 (d, 2H), 7.00 (d, 2H), 7.1-7.2 (m, 9H), 7.47 (d, 2H).

1-(4-Chlorophenyl)-2-phenyl-1-[4-(tetrahydropyranyloxy)phenyl]-butane-1,4-diol

¹H NMR (CDCl₃): 1.5-2.1 (m, 8H), 3.2-4.0 (m, 5H), 5.27 (m, 1H), 6.79 (d,2H), 6.9-7.32 (m, 9H), 7.5 (d, 2H).

1-(4-Chlorophenyl))-[4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-2-phenylbutane-1,4-diol

¹H NMR (CDCl₃): 1.37 and 1.40 and 1.42 and 1.46 (4s, together 6H),1.9-2.1 (m, 2H), 3.2-4.5 (m, 8H), 6.6-7.55 (m, 13H).

1,2-Diphenyl-1-[3-(tetrahydrolpyranyloxy)phenyl]-butane-1,4-diol

is prepared starting fromphenyl-[3-(tetrahydropyranyloxy)phenyl]methanone and cinnamaldehyde. Thecompound is used in the next reaction step without further purification.

c) Dehydration of 1,1,2-Triarylbutane-1,4-diol Derivatives

4-[4-(2-Dimethylaminoethoxy)phenyl]-4-(4-fluorophenyl)-3-phenylbut-3-en-1-ol

1-[4-(2-N,N-Dimethylaminoethoxy)phenyl]-1-(4-fluorophenyl)-2-phenylbutane-1,4-diol(8.46 g, 0.02 mol) is refluxed in 80 ml of acetic anhydride for 3 h. Themixture is cooled to 60° C. and acetyl chloride (7.85 g, 0.1 mol) isadded. The mixture is stirred at 80-90° C. for 4 h. The solvents areevaporated. Solution containing 5% of sodium hydroxide in 80% aqueousmethanol is added and the mixture is stirred for 2 h at RT. Methanol isevaporated. Water is added and the product is extracted into ethylacetate. The organic layer is washed with water, dried and evaporated.The residue (9.5 g) is mixture of E- and Z-isomers of the product. Theisomers are separated by flash chromatography (eluent:toluene:triethylamine 9:1).

E-isomer, ¹H NMR (CDCl₃): 2.27 (s, 6H), 2.64 (t, 2H), 2.74 (t, 2H), 3.57(t, 2H), 3.92 (t, 2H), 6.57 (d, 2H), 6.75 (d, 2H), 7.03 (t, 2H),7.10-7.18 (m, 5H), 7.27 (dd, 2H); Z-isomer, ¹H NMR (CDCl₃): 2.34 (s,6H), 2.74 (t, 2H), 2,79 (t, 2H), 3.60 (t, 2H), 4.05 (t, 2H), 6.69 (t,2H), 6.84 (dd, 2H), 6.91 (d, 2H), 7.09-7.17 (m, 5H), 7.20 (d, 2H).

Using the same method the following compounds are prepared:

4-(4-Chlorophenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]-3-phenylbut-3-en-1-ol

E-isomer, ¹H NMR (CDCl₃): 2.27 (s, 6H), 2.64 (t, 2H), 2.73 (t, 2H), 3.56(t, 2H), 3.91 (t, 2H), 6.56 (d, 2H), 6.74 (d, 2H), 7.10-7.34 (m, 9H).

4-[4-(2-Benzyloxyethoxy)phenyl]-4-(4-fluorohenyl)-3-phenylbut-3-en-1-ol

E-isomer, ¹H NMR (CDCl₃): 2.74 (t, 2H), 3.57 (m, 2H), 3.74 (dist.t, 2H),4.01 (dist.t, 2H), 4.58 (s, 2H), 6.57 (d, 2H), 6.75 (d, 2H), 7.00-7.40(m, 14H) from which the signal 7.03 (t, 2H) can be identified. Z-isomer,¹H NMR (CDCl₃): 2.79 (t, 2H), 3.60 (m, 2H), 3.84 (dist.t, 2H), 4.17(dist.t, 2H), 4.65 (s, 2H), 6.69 (t, 2H), 6.83 (dd, 2H), 6.91 (d, 2H),7.00-7.45 (m, 14H) from which the signal 7.20 (d, 2H) can be identified.

4-[4-(2-Benzyloxyethoxy)phenyl]-3,4-bis(4-chlorophenyl)-but-3-en-1-ol

E-isomer, ¹H NMR (CDCl₃): 2.70 (t, 2H), 3.50-3.65 (m, 2H), 3.75 (dist.t,2H), 4.03 (dist.t, 2H), 4.59 (s, 2H), 6.59 (d, 2H), 6.73 (d, 2H),7.00-7.40 (m, 13H).

3,4-bis(4-Chlorophenyl)-4-[4-(2-hydroxyethoxy)phenyl]but-3-en-1-ol

is produced as a side product in the dehydration reaction of1-[4-(2-benzyloxyethoxy)phenyl]-1,2-bis(4-chlorophenyl)butane-1,4-diol.

E-isomer, ¹H NMR (CDCl₃): 2.72 (t, 2H), 3.50-3.65 (m, 2H), 3.80-3.96 (m,4H), 6.59 (d, 2H), 6.75 (d, 2H), 7.00-7.40 (m, 8H); Z-isomer, ¹H NMR(CDCl₃+MeOH-d₄): 2.75 (t, 2H), 3.56 (t, 2H), 3.95 (t, 2H), 4.09 (t, 2H),6.79 (d, 2H), 6.91 (d, 2H), 7.01 (d, 2H), 7.05 (d, 2H), 7.16 (d. 2H),7.19 (d, 2H).

3,4-bis(4-Chlorophenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]but-3-en-1-ol

E-isomer, ¹H NMR (CDCl₃): 2.29 (s, 6H), 2.66 (t, 2H), 2.72 (t, 2H), 3.57(t, 2H), 3.94 (t, 2H), 6.60 (d, 2H), 6.73 (d, 2H), 7.06 (d, 2H), 7.15(d, 2H), 7.23 (d, 2H), 7.32 (d, 2H); Z-isomer, HCl-salt, ¹H NMR(MeOH-d₄): 2.77 (t, 2H), 3.03 (s, 6H), 3.53 (t, 2H), 3.65 (t, 2H), 4.42(t, 2H), 6.89 (d, 2H), 7.08 (d, 2H), 7.10 (d, 2H), 7.16 (d, 2H), 7.23(d, 2H), 7.31 (d, 2H).

4,4-bis(4-Hydroxyphenyl)-3-phenylbut-3-en-1-ol

The protecting tetrahydropyranyl (THP) groups are removed in thedehydration reaction.

¹H NMR (CDCl₃): 2.76 (t, 2H), 3.54 (m, 2H), 6.46 (d, 2H), 6.70 (d, 2H),6.80 (d, 2H), 7.0-7.2 (m, 7H).

4-(4-Chlorophenyl)-4-(4-hydroxyphenyl)-3-phenylbut-3-en-1-ol

The protecting THP-group is removed in the dehydration reaction.

E-isomer ¹H NMR (CDCl₃): 2.65 (t, 2H), 3.45 (t, 2H), 6.29 (d, 2H), 6.49(d, 2H), 7.00-7.15 (m, 5H), 7.24 (d, 2H), 7.33 (d, 2H); Z-isomer ¹H NMR(CDCl₃): 2.79 (t, 2H), 3.58 (t, 2H), 6.80 (d, 2H), 6.81 (d, 2H), 6.97(d, 2H), 7.1-7.2 (m, 7H).

4-(4-Chlorophenyl)-4-[4-(2,3-dihydroxypropyloxy)phenyl]-3-phenylbut-3-en-1-ol

The 2,2-dimethyl-[1,3]dioxolan ring is cleaved in the reaction.

E-isomer ¹H NMR (CDCl₃): 2.73 (t, 2H), 3.55 (t, 2H), 3.60-3.77 (m, 2H),3.87-4.05 (m, 3H), 6.56 (d, 2H), 6.76 (d, 2H), 7.1-7.35 (m, 9H).

3-(4-Hydroxy-1,2-diphenylbut-1-enyl)phenol

The protecting THP-group is removed in the dehydration reaction.

Z-isomer ¹H NMR (CDCl₃): 2.73 (t, 2H), 3.55 (t, 2H), 6.4-7.4 (m, 12H).

d) Conversion of the Hydroxy Group of 3,3,4-Triarylbut-3-en-1-ols toChlorine

By Thionyl Chloride

(E)-(2-{4-[4-Chloro-1-(4-fluorolphenyl)-2-phenylbut-1-enyl]phenoxy}ethyldimethylamine(No. 1)

(E)-4-[4-(2-Dimethylaminoethoxy)phenyl]-4-(4-fluorophenyl)-3-phenylbut-3-en-1-ol(0.8 g, 2 mmol) is dissolved in toluene (30 ml) and thionyl chloride(0.7 g, 6 mmol) is added. The mixture is refluxed for an hour. Tolueneis partly evaporated. The crystallized hydrochloride salt of the productis filtered off and the precipitate is washed with toluene. The yield is0.79 g, 86%.

¹H NMR (HCl salt, MeOH-d₄): 2.90 (t, 2H), 2.92 (s, 6H), 3.40 (t, 2H),3.49 (dist.t, 2H), 4.21 (dist.t, 2H), 6.70 (d, 2H), 6.85 (d, 2H), 7.11(t, 2H), 7.12-7.22 (m, 5H), 7.32 (dd, 2H).

Using the same method the following compounds are prepared:

(Z)-(2-{4-[4-Chloro-1-(4-fluorophenyl)-2-phenylbut-1-enyl]phenoxy}ethyldimethylamine(No. 2)

¹H NMR (HCl salt, MeOH-d₄): 2.93 (t, 2H), 2.99 (s, 6H), 3.42 (t, 2H),3.61 (dist.t, 2H), 4.39 (dist.t, 2H), 6.73 (t, 2H), 6.88 (dd, 2H), 7.07(d, 2H), 7.12-7.22 (m, 5H), 7.29 (d, 2H).

(E)-(2-{4-[4-Chloro-1-(4-chlorophenyl)-2-phenylbut-1-enyl]phenoxy}ethyl)dimethylamine(No. 3)

¹H NMR (CDCl₃): 2.30 (s, 6H), 2.66 (t, 2H), 2.91 (t, 2H), 3.40 (t, 2H),3.94 (t, 2H), 6.57 (d, 2H), 6.75 (d, 2H), 7.1-7.4 (m, 9H).

(2-{4-[4-Chloro-1,2-bis(4-chlorolphenyl)but-1-enyl]phenoxy}ethyl)dimethylamine(No. 4 and 5)

E-isomer (No. 4), HCl-salt ¹H NMR (CDCl₃): 2.90 (s, 6H), 2.94 (t, 2H),3.40 (t, 4H), 4.38 (t, 2H), 6.59 (d, 2H), 6.78 (d, 2H), 7.06 (d, 2H),7.19 (d, 2H), 7.23 (d, 2H), 7.35 (d, 2H); Z-isomer (No. 5) HCl-salt, ¹HNMR (MeOH-d₄):), 2.95 (t, 2H), 3.41 (s, 6H), 3.41 (t, 2H), 3.48-3.58 (m,2H) 4.56-4.65 (m, 2H), 6.79 (d, 2H), 6.92 (d, 2H), 7.02 (d, 2H), 7.05(d, 2H), 7.19 (d, 2H), 7.22 (d, 2H).

(E)-1-[4-(2-Benzaloxyethoxy)phenyl]-4-chloro-1-(4-fluorophenyl)-2-phenyl-but-1-ene

¹H NMR (CDCl₃): 2.92 (t, 2H), 3.41 (t, 2H), 3.74 (dist.t, 2H), 4.01(dist.t, 2H), 4.59 (s, 2H), 6.58 (d, 2H), 6.76 (d, 2H), 7.06 (t, 2H),7.10-7.40 (m, 12H).

(E)-1-[4-(2-Benzyloxyethoxy)phenyl]-4-chloro-1,2-bis(4-chlorophenyl)-but-1-ene

¹H NMR (CDCl₃): 2.90 (t, 2H), 3.39 (t, 2H), 3.76 (dist.t, 2H), 4.04(dist.t, 2H), 4.60 (s, 2H), 6.60 (d, 2H), 6.74 (d, 2H), 7.06 (d, 2H),7.17 (d, 2H), 7.23 (d, 2H) 7.25-7.4 (m, 7H).

4-Chloro-1-[4-(2-chloroethoxy)phenyl]-1,2-bis(4-chlorophenyl)-but-1-ene(No. 6 and 7)

is prepared from3,4-bis(4-chlorophenyl)-4-[4-(2-hydroxyethoxy)phenyl]but-3-en-1-ol.

E-isomer (No.6), ¹H NMR (CDCl₃): 2.90 (t, 2H), 3.39 (m, 2H), 3.73 (t,2H), 4.10 (t, 2H), 6.59 (d, 2H), 6.76 (d, 2H), 7.10 (d, 2H), 7.17 (d,2H), 7.23 (d, 2H), 7.33 (d, 2H); Z-isomer (No. 7), ¹H NMR (CDCl₃): 2.94(t, 2H), 3.40 (t, 2H), 3.83 (t, 2H), 4.25 (t, 2H), 6.79 (d, 2H), 6.92(d, 2H), 7.02 (d, 2H), 7.05 (d, 2H), 7.18 (d, 2H), 7.20 (d, 2H).

By Triphenylphosphine-carbon Tetrachloride

1-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)phenyl-4-chloro-1-(4-chlorophenyl)-2-phenyl-but-1-ene

Triphenyl phosphine (0.19 g, 0.73 mmol) is dissolved in acetonitrile (4ml). Carbon tetrachloride (0.237 g, 1.3 mmol) and triethylamine (0.043g, 0.43 mmol) is added to the solution and the mixture is stirred forhalf an hour at ambient temperature.4-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)phenyl-4-(4-chlorophenyl)-3-phenyl-but-3-en-1-ol(0.2 g, 0.43 mmol, prepared from4-(4-chlorophenyl)-4-[4-(2,3-di-hydroxypropyloxy)phenyl]-3-phenyl-but-3-n-1-olby protecting the diol group as acetonide) is dissolved in acetonitrile,added to the reaction mixture and stirring is continued for additional 2hours. Then the solvent is evaporated and the residue is dissolved in 20ml of methanol-water-solution (8:2). Solution is extracted twice withpetroleum ether (20 ml) at boiling point. Petroleum ether phases arecombined and washed once again with hot methanol-water solution. Yield0.07 g.

E-isomer ¹H NMR (CDCl₃): 1.37 and 1.41 (2s, together 6H), 2.91 (t, 2H),3.40 (t, 2H), 3.70-4.14 (m, 4H), 4.39 (quintet, 1H), 6.56 (d, 2H), 6.76(d, 2H), 7.05-7.4 (m, 9H).

e) Removal of the Protecting Groups

(E)-2-{4-[4-Chloro-2-phenyl-1-(4-fluorophenyl)but-1-enyl]phenoxy}ethanol(No. 8)

(E)-1-[4-(2-Benzyloxyethoxy)phenyl]-4-chloro-1-(4-fluorophenyl)-2-phenyl-but-1-ene(400 mg, 0.8 mmol) is dissolved in toluene. Zn (106 mg, 1.6 mmol) andacetyl chloride (126 mg, 1.6 mmol) are added under nitrogen atmosphere.The mixture is stirred at room temperature for 6 h. The mixture isfiltered and the solvent evaporated. The residue is dissolved in 80%aqueous methanol containing 5% of sodium hydroxide. The mixture isstirred at room temperature for 2 h and methanol is evaporated. Somewater is added and the product is extracted into ethyl acetate. Themixture is dried and the solvent is evaporated. The product is purifiedby flash chromatography (eluent toluene:methanol 9:1).

¹H NMR (CDCl₃): 2.92 (t, 2H), 3.41 (t, 2H), 3.87-3.95 (m, 4H), 6.57 (d,2H), 6.78 (d, 2H), 7.06 (t, 2H), 7.10-7.31 (m, 7H).

Using the same method the following compound included in the inventionis prepared:

(E)-2-{4-[(Z)-4-Chloro-1,2-bis(4-chlorophenyl)but-1-enyl]phenoxy}ethanol(No. 9)

¹H NMR (CDCl₃): 2.90 (t, 2H), 3.39 (t, 2H), 3.85-4.05 (m, 4H), 6.61 (d,2H), 6.77 (d, 2H), 7.07 (d, 2H), 7.1-7.26 (m, 4H), 7.35 (d, 2H).

(E)-3-{4-[(Z)-4-Chloro-1-(4-chlorophenyl)-2-phenyl-but-1-enyl]phenoxy}propane-1,2-diol(No. 10)

1-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)phenyl-4-chloro-1-(4-chlorophenyl)-2-phenyl-but-1-ene(0.5 g, 1.0 mmol) is dissolved in ethanol and 2 N aqueous hydrogenchloride (5 ml) is added to the solution. The mixture is heated to 40°C. and stirring is continued for an hour. Then ethanol is evaporated andthe product is extracted in toluene, which is washed with water, driedand evaporated to dryness. Yield 0.45 g.

¹H NMR (CDCl₃): 2.91 (t, 2H), 3.41 (t, 2H), 3.60-4.15 (m, 5H), 6.56 (d,2H), 6.77 (d, 2H), 7.1-7.4 (m, 9H).

Example 2 a) O-alkylation of 4-(1,2-Diaryl-4-hydroxybut-1-enyl)phenolDerivatives

4,4-bis[4-(2-Benzyloxyethoxy)phenyl]-3-phenylbut-3-en-1-ol

is prepared from 4,4-bis(4-hydroxyphenyl)-3-phenylbut-3-en-1-ol (example1c) and benzyl 2-bromoethyl ether by PTC reaction according to themethod described in the example 1a.

¹H NMR (CDCl₃): 2.78 (t, 2H), 3.59 (q, 2H), 3.74, 3.84, 4.02 and 4.17 (4dist.t, together 8H), 4.59 (s, 2H), 4.65 (s, 2H), 6.56 (d, 2H), 6.76 (d,2H), 6.91 (d, 2H), 7.09-7.40 (m, 17H).

Using the same method the following compounds are prepared:

(E)-4-[4-(2-Benzyloxyethoxy)phenyl]-4-(4-chlorophenyl)-3-phenyl-but-3-en-1-ol

¹H NMR (CDCl₃): 2.74 (t, 2H), 3.56 (t, 2H), 3.71-3.76 (m, 2H), 3.98-4.03(m, 2H), 4.60 (s, 2H), 6.57 (d, 2H), 6.75 (d, 2H), 7.10-7.40 (m, 14H).

(Z)-4-[3-(2-Benzyloxyethoxy)phenyl]-3,4-diphenyl-but-3-en-1-ol

¹H NMR (CDCl₃): 2.75 (t, 2H), 3.58 (t, 2H), 3.63-3.66 (m, 2H), 3.81-3.85(m, 2H), 4.55 (s, 2H), 6.47-7.40 (m, 19H).

(Z)-4-[4-(2-Methylsulfanylethoxy)phenyl]-3,4-diphenyl-but-3-en-1-ol

The compound is prepared by using the method described in the example 1astarting from 4-(4-hydroxyphenyl)-3,4-diphenyl-but-3-en-1-ol(preparation described in U.S. Pat. No. 4,996,225) and 2-chloroethylmethyl sulfide.

¹H NMR (CDCl₃): 2.16 (s, 3H), 2.75 (t, 2H), 2.79 (t, 2H), 3.59 (q, 2H),4.02 (t, 2H), 6.55 (d, 2H), 6.79 (d, 2H), 7.05-7.40 (m, 10H).

(Z)-4-[4-(3-Benzyloxypropoxy)phenyl]-3,4-diphenyl-but-3-en-1-ol

is prepared by the same method using benzyl 3-bromopropyl ether as areagent.

¹H NMR (CDCl₃): 2.00 (quint., 2H), 2.75 (t, 2H), 3.59 (2×t, 4H), 3.95(t, 2H), 4.48 (s, 2H), 6.54 (d, 2H), 6.78 (d, 2H), 7.11-7.40 (m, 15H).

(E)-4-(4-Chlorophenyl)-3-phenyl-4-(4-{2-[2-(tetrahydropyranyloxy)ethoxy]ethoxy}phenyl)but-3-en-1-ol

NaH (0.09 g, 2.69 mmol) is mixed with dimethylformamide (DMF) (30 ml).(E)-4-(4-Chlorophenyl)-4-(4-hydroxyphenyl)-3-phenylbut-3-en-1-ol isdissolved in the solution and the mixture is heated to 60° C. andstirred for half an hour. 2-[(2-(Tetrahydropyranyloxy)ethoxy]ethylchloride (0.83 g, 4.03 mmol) dissolved in DMF (5 ml) is added to thesolution and heating is continued for 3 hours. Saturated aqueousammonium chloride solution (30 ml) and toluene (30 ml) is added to thecooled reaction mixture and stirring is continued for 10 minutes. Layersare separated and aqueous layer is extracted with toluene (30 ml).Toluene phases are combined and washed with 2 N aqueous sodium hydroxideand three times with water. Organic phase is dried and evaporated todryness. Yield 1.4 g, 99%.

¹H NMR (CDCl₃): 1.40-1.90 (m, 6H), 2.70 (t, 2H), 3.4-3.94 (m, 10H),3.95-4.05 (m, 2H), 4.55 (m, 1H), 6.56 (d, 2H), 6.74 (d, 2H), 7.05-7.35(m, 9H).

Using the same method the following compounds are prepared:

(Z)-3,4-Diphenyl-4-(4-{2-[(2-(tetrahydropyranyloxy)ethoxy]ethoxy}phenyl)but-3-en-1-ol

is prepared by the same method as previous compound starting from4-(4-hydroxyphenyl)-3,4-diphenyl-but-3-en-1-ol (preparation described inU.S. Pat. No. 4,996,225) and 2-[2-(tetrahydropyranyloxy)ethoxy]ethylchloride

¹H NMR (CDCl₃): 1.40-1.91 (m, 6H), 2.74 (t, 2H), 3.4-4.0 (m, 12H), 4.61(m, 1H), 6.55 (d, 2H), 6.77 (d, 2H), 7.05-7.35 (m, 10H).

4-(4-Fluorophenyl)-3-phenyl-4-(4-{2-[2-(tetrahydropyranyloxy)ethoxy]ethoxy}phenyl)but-3-en-1-ol

E-isomer ¹H NMR (CDCl₃): 1.38-1.90 (m, 6H), 2.75 (t, 2H), 3.32-4.03 (m,10H), 4.00 (m, 2H), 4.62 (m, 1H), 6.56 (d, 2H), 6.75 (d, 2H), 7.04 (t,2H), 7.00-7.20 (m, 5H), 7.27 (dd, 2H); Z-isomer ¹H NMR (CDCl₃):1.40-1.90 (m, 6H), 2.79 (t, 2H), 3.43-4.03 (m, 10H), 4.15 (m, 2H), 4.65(m, 1H), 6.69 (t, 2H), 6.83 (dd, 2H), 6.90 (d, 2H), 7.05-7.20 (m, 5H),7.19 (d, 2H).

(Z)4-[4-(2,2-Dimethyl-[1,3]-dioxolan-4-ylmethoxy)phenyl]-3,4-diphenylbut-3-en-1-ol

¹H NMR (CDCl₃): 1.37 and 1.41 (2s, together 6H), 2.75 (t, 2H), 3.58 (t,2H), 3.70-4.10 (m, 4H), 4.39 (quintet, 1H), 6.56 (d, 2H), 6.78 (d, 2H),7.10-7.40 (m, 10H).

{4-[1-(4-Chlorophenyl)-4-hydroxy-2-phenylbut-1-enyl]phenoxy}acetic AcidEthyl Ester

is prepared from4-(4-chlorophenyl)-4-(4-hydroxyphenyl)-3-phenylbut-3-en-1-ol (example1c.) and ethyl bromoacetate according to the procedure described in theexample 1a using NaH as a base.

E-isomer ¹H NMR (CDCl₃): 1.25 (t, 3H), 2.74 (t, 2H), 3.57 (t, 2H), 4.22(q, 2H), 4.48 (s, 2H), 6.56 (d, 2H), 6.77 (d, 2H), 7.0-7.4 (m, 9H);Z-isomer ¹H NMR (CDCl₃): 1.31 (t, 3H), 2.78 (t, 2H), 3.58 (t, 2H), 4.29(q, 2H), 4.63 (s, 2H), 6.79 (d, 2H), 6.89 (d, 2H), 6.98 (d, 2H),7.15-7.30 (m, 7H).

b) Conversion of the Hydroxyl Group to Chlorine

1-bis[4-(2-Benzyloxyethoxy)phenyl]-4-chloro-2-phenyl-but-1-ene

Conversion of the hydroxy group to chlorine is carried out using thionylchloride as a reagent according to the procedure described in theexample 1d.

¹H NMR (CDCl₃): 2.94 (t, 2H), 3.42 (t, 2H), 3.73 and 3.83 (2 dist.t.,together 4H), 4.00 and 4.16 (2 dist.t., together 4H), 4.58 (s, 2H), 4.65(s, 2H), 6.56 (d, 2H), 6.76 (d, 2H), 6.92 (d, 2H), 7.10-7.40 (m, 17H).

Using the same method the following compounds are prepared:

(E)-1-[4-(2-Benzaloxyethoxy)phenyl]4-chloro-1-(4-chlorophenyl)-2-phenyl-but-1-ene

¹H NMR (CDCl₃): 2.91 (t, 2H), 3.40 (t, 2H), 3.71-3.76 (m, 2H), 3.98-4.03(m, 2H), 4.60 (s, 2H), 6.57 (d, 2H), 6.75 (d, 2H), 7.10-7.40 (m, 14H).

(Z)-4-Chloro-1-[4-(2-methylsulfanylethoxy)phenyl]-1,2-diphenyl-but-1-ene(No. 11)

¹H NMR (CDCl₃): 2.16 (s, 3H), 2.79 (t, 2H), 2.92 (t, 2H), 3.42 (t, 2H),4.01 (t, 2H), 6.55 (d, 2H), 6.78 (d, 2H), 7.05-7.45 (m, 10H).

(Z)-1-[3-(2-Benzyloxyethoxy)phenyl]-4-chloro-1,2-diphenyl-but-1-ene

¹H NMR (CDCl₃): 2.92 (t, 2H), 3.41 (t, 2H), 3.63-3.67 (m, 2H), 3.81-3.85(m, 2H), 4.55 (s, 2H), 6.47-7.40 (m, 19H).

(Z)-1-[4-(3-Benzyloxypropoxy)phenyl]-4-chloro-1,2-diphenyl-but-1-ene

¹H NMR (CDCl₃): 2.0 (quintet, 2H), 2.92 (t, 2H), 3.42 (t, 2H), 3.59 (t,2H), 3.94 (t, 2H), 4.48 (s, 2H), 6.54 (d, 2H), 6.78 (d, 2H), 7.11-7.40(m, 15H).

{4-[4-Chloro-1-(4-chlorophenyl)-2-phenylbut-1-enyl]phenoxy}acetic AcidEthyl Ester and the Corresponding Acid (No. 12 and 13)

E-isomer, ethyl ester ¹H NMR (CDCl₃): 1.25 (t, 3H), 2.91 (t, 2H), 3.41(t, 2H), 4.21 (q, 2H), 4.49 (s, 2H), 6.57 (d, 2H), 6.77 (d, 2H), 7.0-7.4(m, 9H).

The ester is hydrolyzed to the corresponding acid in 80% aqueousmethanol containing 5% of sodium hydroxide.

E-isomer, acid (No. 12) ¹H NMR (CDCl₃): 2.91 (t, 2H), 3.41 (t, 2H), 4.47(s, 2H), 6.58 (d, 2H), 6.78 (d, 2H), 7.0-7.4 (m, 9H); Z-isomer ethylester ¹H NMR (CDCl₃): 1.31 (t, 3H), 2.95 (t, 2H), 3.42 (t, 2H), 4.30 (q,2H), 4.65 (s, 2H), 6.79 (d, 2H), 6.91 (d, 2H), 6.98 (d, 2H), 7.15-7.30(m, 2H); Z-isomer, acid (No. 13) ¹H NMR (CDCl₃): 2.95 (t, 2H), 3.41 (t,2H), 4.65 (s, 2H), 6.79 (d, 2H), 6.94 (d, 2H), 6.98 (d, 2H), 7.10-7.30(m, 7H).

(Z)-1,2-Diphenyl-4-chloro-4-(4-{2-[2-(tetrahydropyranyloxy)ethoxy]ethoxy}phenyl)-but-1-ene

Conversion of hydroxy group to chlorine is carried out using Ph₃P andCCl₄ as reagents according to the procedure described in the example 1d.

¹H NMR (CDCl₃): 1.30-1.90 (m, 6H), 2.92 (t, 2H), 3.42 (t, 2H), 3.4-4.0(m, 10H), 4.62-4.65 (m, 1H), 6.55 (d, 2H), 6.77 (d, 2H), 7.05-7.35 (m,10H).

Using the same method the following compounds are prepared:

(Z)-4-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxymethyl]-2,2-dimethyl-[1,3]dioxolane

¹H NMR (CDCl₃): 1.37 and 1.41 (2s, together 6H), 2.91 (t, 2H), 3.41 (t,2H), 3.7-4.1 (m, 4H), 4.39 (quintet, 1H), 6.55 (d, 2H), 6.77 (d, 2H),7.10-7.41 (m, 10H).

(E)-1-(4-{2-[(2-Chloroethoxy]ethoxy}phenyl)-4-chloro-1-(4-chlorophenyl)-2-phenyl-but-1-ene(No. 14)

The tetrahydropyranyloxy group is also converted to chlorine in thereaction.

¹H NMR (CDCl₃): 2.94 (t, 2H), 3.43 (t, 2H), 3.65 (dist. t, 2H), 3.8-3.85(m, 4H), 4.0-4.06 (m, 2H), 6.60 (d, 2H), 6.78 (d, 2H), 7.10-7.40 (m,9H).

(E)-1-(4-{2-[(2-Chloroethoxy]ethoxy}phenyl)-4-chloro-1-(4-fluorophenyl)-2-phenyl-but-1-ene(No. 15)

The tetrahydropyranyloxy group is also converted to chlorine in thereaction.

¹H NMR (CDCl₃): 2.91 (t, 2H), 3.41 (t, 2H), 3.62 (dist. t, 2H),3.74-3.85 (m, 4H), 4.01 (dist.t, 2H), 6.57 (d, 2H), 6.76 (d, 2H), 7.06(t, 2H), 7.09-7.22 (m, 5H), 7.27 (dd, 2H)

c) Removal of the Protecting Groups

2-(4-{4-Chloro-1-[4-(2-hydroxyethoxy)phenyl]-2-phenyl-but-1-enyl}phenoxy)-1-ethanol(No. 16)

The benzyl groups are removed using Zn and AcCl as reagents according tothe method described in the example 1e.

¹H NMR (CDCl₃): 2.95 (t, 2H), 3.42 (t, 2H), 3.80-4.20 (m, 8H), 6.56 (d,2H), 6.78 (d, 2H), 6.92 (d, 2H), 7.10-7.26 (m, 7H).

Using the same method the following compounds included in the inventionare prepared:

(E)-2-{4-[4-Chloro-2-phenyl-1-(4-chlorophenyl)but-1-enyl]phenoxy}ethanol(No. 17)

¹H NMR (CDCl₃): 2.92 (t, 2H), 3.41 (t, 2H), 3.80-4.00 (m, 4H), 6.57 (d,2H), 20 6.77 (d, 2H), 7.10-7.40 (m, 9H).

(Z)-2-[3-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol (No. 18)

¹H NMR (CDCl₃): 2.93 (t, 2H), 3.41 (t, 2H), 3.70-3.80 (m, 4H), 6.40-7.40(m, 14H).

(Z)-2-{2-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol (No.19)

The tetrahydropyranyl ether is cleaved with H⁺/EtOH using the methoddescribed in the example 1e.

¹H NMR (CDCl₃): 2.92 (t, 2H), 3.41 (t, 2H), 3.61, 3.68, 3.77 (3 dist.t,6H), 4.00 (dist.t, 2H), 6.56 (d, 2H), 6.78 (d, 2H), 7.1-7.4 (m, 10H).

Using the same method the following compound included in the inventionis prepared:

(Z)-3-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]propane-1,2-diol (No.20)

¹H NMR (CDCl₃): 2.92 (t, 2H), 3.41 (t, 2H), 3.58-4.10 (m, 5H), 6.53 (d,2H), 6.78 (d, 2H), 7.10-7.41 (m, 10H).

Example 3 a)(Z)-4-[4-(2-Imidazol-1-yl-ethoxy)phenyl]-3,4-diphenyl-but-3-en-1-ol

(Z)-4-[4-(2-Bromoethoxy)phenyl]-3,4-diphenylbut-3-en-1-ol (preparationdescribed in U.S. Pat. No. 4,996,225) (4.97 g, 0.0117 mol) is dissolvedin methyl ethyl ketone (50 ml) and potassium carbonate (4.8 g, 0.035mol) and imidazole sodium salt (2.1 1 g, 0.0234 mol) is added to thesolution. Mixture is stirred and refluxed for five hours. Then thesolution is filtered and the filtrate is evaporated to dryness. Theresidue is dissolved in ethyl acetate, washed with 2 N aqueous sodiumhydroxide solution and with water, dried and evaporated to dryness. Theresidue is recrystallized from the mixture of toluene and acetonitrile.

¹H NMR (CDCl₃): 2.75 (t, 2H), 3.59 (dist. t, 2H), 4.07 (dist. t, 2H),4.23 (dist. t, 2H), 6.51 (d, 2H), 6.79 (d, 2H), 6.97 (s, 1H), 7.03 (s,1H), 7.05-7.40 (m, 10H), 7.51 (s, 1H).

(Z)-4-[4-(2-Methylaminoethoxy)phenyl]-3,4-diphenylbut-3-en-1-ol

(Z)-4-[4-(2-Chloroethoxy)phenyl]-3,4-diphenylbut-3-en-1-ol (prepared as(Z)-4-[4-(2-bromoethoxy)phenyl]-3,4-diphenylbut-3-en-1-ol preparation ofwhich is described in U.S. Pat. No. 4,996,225) (2.0 g, 0.0052 mol) andmethyl amine in 40% aqueous solution (5 ml, 0.065 mol) is mixed withdimethylformamide (8 ml). Mixture is heated in a sealed tube at 60° C.for 8 hours. To the mixture is added 60 ml of water and extracted withethyl acetate. Ethyl acetate phase is washed with aqueous 2 N hydrogenchloride solution. Water phase is made alkaline with 2 N sodiumhydroxide solution and extracted with ethyl acetate. Ethyl acetate phaseis washed with water, dried with magnesium sulfate and evaporated todryness. Yield 1.5 g.

¹H NMR (CDCl₃): 2.39 (s, 3H), 2.70 (t, 2H), 2.84 (t, 2H), 3.48 (t, 2H),3.93 (t, 2H), 6.59 (d, 2H), 6.77 (d, 2H), 7.10-7.40 (m, 10H).

b)(Z)-4-(4-{2-[(2-Benzyloxyethyl)methylamino]ethoxy}phenyl)-3,4-diphenyl-but-3-en-1-ol

Prepared by using the same PTC method as in the example 1a using benzyl2-bromoethyl ether as a reagent.

¹H NMR (CDCl₃): 2.35 (s, 3H), 2.70, 2.75, 2,79 (3 t, 6H), 3.56 (t, 2H),3.60 (t, 2H), 3.94 (t, 2H), 4.50 (s, 2H), 6.54 (d, 2H), 6.77 (d, 2H),7.10-7.20 (m, 5H), 7.27-7.35 (m, 10H).

c)(Z)-1-{2-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]ethyl}-1H-imidazole(No. 21)

is prepared according to the example 1d using triphenylphosphine andcarbon tetrachloride as reagents. Purification of product is made byevaporating acetonitrile and dissolving the residue to acidicmethanol-water (8:2) solution and extracting triphenylphosphine withtoluene (three times, at room temperature). Methanol-water-solution wasmade alkaline and the product was extracted with toluene. Toluene phasewas washed twice with water and evaporated to dryness. The product wascrystallized from ethyl acetate as HCl-salt. Yield 46%.

¹H NMR (HCl-salt, MeOH-d₄): 2.89 (t, 2H), 3.39 (t, 2H), 4.23 (t, 2H),4.60 (t, 2H), 6.60 (d, 2H), 6.80 (d, 2H), 7.10-7.40 (m, 10H), 7.54 (s,1H), 7.67 (s, 1H), 8.98 (s, 1H).

(Z)-(2-Benzyloxyethyl)-{2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy-ethyl]methylamineis prepared according to example 1d using thionyl chloride as a reagent.

¹H NMR (CDCl₃): 2.35 (s, 3H), 2.70, 2.79 (2 t, 4H), 2.92 (t, 2H), 3.42(t, 2H), 3.56 (t, 2H), 3.93 (t, 2H), 4.51 (s, 2H), 6.54 (d, 2H), 6.77(d, 2H), 7.10-7.40 (m, 15H).

d)(Z)-2-({2-[-4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethyl}methylamino)ethanol(No. 22)

is prepared by the same method as 1e using Zn and acetyl chloride asreagents.

¹H NMR (CDCl₃): 2.32 (s, 3H), 2.60 (t, 2H), 2.78 (t, 2H), 2.92 (t, 2H),3.42 (t, 2H), 3.57 (t, 2H), 3.91 (t, 2H), 6.54 (d, 2H), 6.78 (d, 2H),7.05-7.40 (m, 10H).

Example 4 a) 2-(4-Chlorophenyl)-1-(4-methoxyphenyl)ethanone

Anisole (13.9 g, 0.13 mol) is added to a stirred solution of4-chlorophenylacetic acid (20.0 g, 0.12 mol) in trifluoroaceticanhydride (16.5 ml, 0.12 mol). The mixture is stirred in roomtemperature for 24 h. Ice water is added and the crystallized product iscollected on a sinter and washed with water. The product isrecrystallized from ethanol. The yield is 20.4 g, 67%.

¹H NMR (CDCl₃): 3.86 (s, 3H), 4.20 (s, 2H), 6.93 (d, 2H), 7.20 (d, 2H);7.28 (d, 2H), 7.98 (d, 2H).

Using the same method the following compounds are prepared:

2-(4-Fluorophenyl)-1-(4-methoxyphenyl)ethanone

¹H NMR (CDCl₃): 3.87 (s, 3H), 4.21 (s, 2H), 6.94 (d, 2H), 7.01 (t, 2H),7.22 (dd, 2H), 7.99 (d, 2H).

1-(4-Methoxyphenyl)-2-phenyl-ethanone

¹H NMR (CDCl₃): 3.84 (s, 3H), 4.23 (s, 2H), 6.92 (d, 2H), 7.20-7.40 (m,5H), 7.99 (d, 2H).

b) 2-(4-Chlorophenyl)-1-(4-hydroxyphenyl)ethanone

Aluminum chloride (29.8 g, 0.223 mol) is added in small portions to astirred solution of 2-(4-chlorophenyl)-1-(4-methoxyphenyl)ethanone (19.4g, 0.074 mol) in toluene (300 ml). The mixture is heated to 60° C. andstirring is continued for 2 h. Dilute hydrochloric acid is added to thecooled mixture. Ethyl acetate is added to dissolve the product. Thelayers are separated and the aqueous phase is extracted with ethylacetate. The combined organic phases are dried and the solvents areevaporated. The product is recrystallized from toluene. The yield is 17g, 93%.

¹H NMR (CDCl₃+MeOH-d₄): 4.19 (s, 2H), 6.85 (d, 2H), 7.19 (d, 2H), 7.28(d, 2H), 7.90 (d, 2H).

Using the same method the following compounds are prepared:

2-(4-Fluorophenyl)-1-(4-hydroxyphenyl)ethanone

¹H NMR (CDCl₃+MeOH-d₄): 4.20 (s, 2H), 6.86 (d, 2H), 7.00 (t, 2H), 7.22(dd, 2H), 7.91 (d, 2H).

1-(4-Hydroxyphenyl)-2-phenylethanone

¹H NMR (CDCl₃+MeOH-d₄): 4.20 (s, 2H), 6.84 (d, 2H), 7.2-7.4 (m, 5H) 7.90(d, 2H).

c) O-alkylation of 4-Hydroxydesoxybenzoin Derivatives

In PTC-conditions

2-(4-Chlorophenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]ethanone

10% Aqueous sodium hydroxide is added to the mixture containing2-(4-chlorophenyl)-1-(4-hydroxyphenyl)ethanone (6.0 g, 0.024 mol), TBABr(0.9 g) in toluene (60 ml) at 60° C. The mixture is stirred for 30 min.N,N-Dimethylaminoethyl chloride hydrochloride (3.6 g, 0.025 mol) isadded and stirring is continued at 70-75° C. for 3 h. The layers areseparated and the aqueous phase is extracted with toluene. The combinedtoluene phases are evaporated to give the product (1.85 g, 24%).

¹H NMR (CDCl₃): 2.34 (s, 6H), 2.75 (t, 2H), 4.12 (t, 2H), 4.20 (s, 2H),6.95 (d, 2H), 7.19 (d, 2H), 7.29 (d, 2H), 7.97 (d, 2H).

Using the same method the following compound is prepared:

1-[4-(2-Dimethylaminoethoxy)phenyl]-2-(4-fluorophenyl)ethanone

¹H NMR (CDCl₃): 2.34 (s, 6H), 2.75 (t, 2H), 4.12 (t, 2H), 4.21 (s, 2H),6.96 (d, 2H), 7.01 (t, 2H), 7.22 (dd, 2H), 7.98 (d, 2H).

With K₂CO₃ in 2-Butanone

1-[4-(2-Benzyloxyethoxy)phenyl]-2-phenylethanone1-(4-Hydroxyphenyl)-2-phenylethanone (17 g, 0.08 mol) is dissolved in2-butanone (200 ml) and potassium carbonate (33.1 g, 0.24 mol) and2-benzyloxyethyl bromide (25.8 g, 0.12 mol) is added to the solution.Mixture is stirred and refluxed for three hours. Then the solution isfiltered and the filtrate is evaporated to dryness. The residue isdissolved in toluene, washed with 2 N aqueous sodium hydroxide solutionand with water, dried and evaporated to dryness. The product iscrystallized from ethanol. Yield 23.2 g, 84%.

¹H NMR (CDCl₃): 3.80-3.86 (m, 2H), 4.2054.22 (m, 2H), 4.23 (s, 2H), 4.63(s, 2H), 6.90 (d, 2H), 7.20-7.40 (m, 10H), 7.90 (d, 2H).

Using the same method the following compounds are prepared:

1-[4-(2-Benzyloxyethoxy)phenyl]-2-(4-chlorophenyl)ethanone

¹H NMR (CDCl₃): 3.84 (dist.t., 2H), 4.20 (dist.t., 22), 4.20 (s, 2H)),4.63 (s, 2H), 6.95 (d, 2H), 7.19 (d, 2), 7.29 (d, 2H), 7.30-7.45 (m, 5)7.96 (d, 2H).

2-(3-Methoxyphenyl)-1-[4-(2-piperidan-1-ylethoxy)phenyl]ethanone

1-(4-hydroxyphenyl)-2-(3-methoxyphenyl)ethanone and1-(2-chloroethyl)piperidine hydrochloride are used as startingmaterials.

¹H NMR (CDCl₃): 1.37-1.52 (m, 2H), 1.52-1.68 (m, 4H), 2.50 (br.t, 4H),2.78 (t, 2H), 3.77 (s, 3H), 4.14 (t, 2H), 4.19 (s, 2H), 6.73-6.90 (m,311), 6.90 (d, 2H), 7.22 (t, 1H), 7.96 (d, 2H).

2-(2-Methoxyphenyl)-1-[4-(2-piperidin-1-ylethoxy)phenyl]ethanone

1-(4-hydroxyphenyl)-2-(2-methoxyphenyl)ethanone and1-(2-chloroethyl)piperidine hydrochloride are used as startingmaterials.

¹H NMR (CDCl₃): 1.40-1.53 (m, 2H), 1.53-1.70 (t , 4H), 2.51 (br.t, 4H),2.79 (t, 2H), 3.79 (s, 3H), 4.16 (t, 2H), 4.22 (s, 2H), 6.84-7.00 (m,together 4H) under which 6.92 (d, 2H), 7.14-7.30 (m, 2H), 8.00 (d, 2H).

d) C-alkylation of Desoxybenzoin Derivatives

4-Benzyloxy-2-(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]butan-1-one

The mixture containing2-(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]ethanone (6.3 g,0.020 mol) and TBABr (0.5 g) in toluene (70 ml) is heated to 70° C. and48% aqueous sodium hydroxide (70 ml) is added. The mixture is stirredfor 30 min. and (2-bromoethoxymethyl)benzene (5.5 g, 0.025 mol) is addeddropwise at 85-90° C. The reaction mixture is stirred at 95-100° C. for3 h. The layers are separated and the aqueous phase is extracted withtoluene. The combined organic phases are washed with water and thesolvent is evaporated. The residual product (9.0 g) is used in the nextreaction step without further purification.

¹H NMR (CDCl₃): 1.93-2.15 and 2.38-2.58 (2m, together 2H), 2.32 (s, 6H),2.72 (t, 2H), 3.25-3.55 (m, 2H), 4.08 (t, 2H), 4.42 (s, 2H), 4.82 (t,1H), 6.88 (d, 2H), 7.15-7.40 (m, 9H), 7.92 (d, 2H).

Using the same method the following compounds are prepared:

4-Benzyloxy-1-[4-(2-dimethylaminoethoxy)phenyl]-2-(4-fluorophenyl)butan-1-one

¹H NMR (CDCl₃): 1.95-2.15 and 2.40-2.60 (2m, together 2H), 2.31 (s, 6H),2.71 (t, 2H), 3.25-3.55 (m, 2H), 4.07 (t, 2H), 4.42 (s, 2H), 4.83 (t,1H), 6.88 (d, 2H), 6.94 (t, 2H), 7.10-7.40 (m, 7H), 7.93 (d, 2H).

4-Benzaloxy-2-(4-chlorophenyl)-1-(4-methoxyphenyl)butan-1-one

¹H NMR (CDCl₃): 1.95-2.15 and 2.35-2.55 (2m, together 2H), 3.30-3.55 (m,2H), 3.82 (s, 3H), 4.42 (s, 2H), 4.82 (t, 1H), 6.85 (d, 2H), 7.10-7.40(m, 9H), 7.93 (d, 2H).

1-[4-(2-Benzyloxyethoxy)phenyl]-2-phenyl-4-(tetrahydropyranyloxy)butan-1-one

¹H NMR (CDCl₃): 1.4-1.9 (m, 6H), 2.0-2.2 (m, 1H), 2.4-2.65 (m, 1H),3.2-4.05 (m, 6H), 4.1-4.2 (m, 2H), 4.45-4.5 (m, 1H), 4.60 (s, 2H), 4.80(t, 1H), 6.88 (d, 2H), 7.1-7.4 (m, 10H), 7.96 (d, 2H).

1-[4-(2-Benzyloxyethoxy)phenyl]-2-(4-chlorophenyl)-4-(tetrahydropyranyloxy)butan-1-one

¹H NMR (CDCl₃): 1.30-1.90 (m, 6H), 1.95-2.15 and 2.38-2.58 (2m, together2H), 3.20-4.05 (m, 6H), 4.16 (dist.t., 2H), 4.75-4.85 (m, 1H), 4.61 (s,2H), 4.80 (t, 1H), 6.88 (d, 2H), 7.13-7.40 (m, 9H), 7.94 (d, 2H).

1,2-Bisphenyl-4-(tetrahydropyranyloxy)butan-1-one

¹H NMR (CDCl₃): 1.4-1.9 (m, 6H), 2.0-2.2 (m, 1H), 2.4-2.65 (m, 1H),3.2-3.9 (m, 4H), 4.45-4.5 (m, 1H), 4.85 (t, 1H), 7.1-7.5 (m, 8H), 8.00(d, 2H).

2-(3-Methoxyphenyl)-1-[4-(2-piperidin-1-ylethoxy)phenyl]-4-(tetrahydropyranyloxy)butan-1-one

¹H NMR (CDCl₃): 1.40-1.90 (m, 13H), 1.95-2.2 (m, 1H), 2.48 (br.t, 4H),2.75 (t, 2H), 3.20-3.90 (m, 4H) under which 3.76 (s, 3H), 4.11 (t, 2H),4.49 (m, 1H), 4.77 (m, 1H), 6.73 (dd, 2H), 6.80-6.95 (m, 4H), 7.21 (t,1H), 7.96 (d, 2H).

2-(2-Methoxyphenyl)-1-[4-(2-piperidin-1-ylethoxy)phenyl]-4-(tetrahydropyranyloxy)butan-1-one

¹H NMR (CDCl₃): 1.30-1.90 (m, 13H), 1.95-2.15 (m, 1H), 2.48 (m, 4H),2.74 (t, 2H), 3.20-4.00 (m, 4H) under which 3.88 (s, 3H), 4.09 (t, 2H),4.45-4.55 (m, 1H), 5.22 (m, 1H), 6.73-6.90 (m, 4H) 7.14-7.30 (m, 2H),7.97 (d, 2H).

e) Grignard Reaction With Desoxybenzoin Derivatives

4-Benzyloxy-2-(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]-1-phenylbutan-1-ol

4-Benzyloxy-2-(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]butan-1-one(9.4 g, 0.021 mol) is added to Grignard reagent prepared frombromobenzene (13.1 g, 0.083 mol) and Mg turnings (2.0 g, 0.083 mol) indry tetrahydrofuran. The mixture is refluxed for 3 h. Saturated ammoniumchloride solution is added to the cooled reaction mixture, the THF layeris separated and the aqueous phase is extracted with toluene. Thecombined organic phases are washed with water and the solvents areevaporated. The residual product (10.7 g) is used in the next reactionstep without further purification.

Using the same method the following compounds are prepared:

4-Benzyloxy-1-[4-(2-dimethylaminoethoxy)phenyl]-2-(4-fluorophenyl)-1-phenylbutan-1-ol

is used in the next reaction step without further purification.4-Benzyloxy-2-(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-methoxyphenyl)butan-1-ol

is used in the next reaction step without further purification.

1-(3-Benzyloxyphenyl)-1-[4-(2-benzyloxyethoxy)phenyl]-2-phenyl-4-(tetrahydropyranyloxy)butan-1-ol

is used in the next reaction step without further purification.

1-[4-(Benzyloxyethoxy)phenyl]-2-(4-chlorophenyl)-1-(4-methoxyphenyl)-4-(tetrahydropyranyloxy)butan-1-ol

is used in the next reaction step without further purification.

2-(3-Methoxyphenyl)-1-phenyl-1-[4-(2-piperidin-1-ylethoxy)phenyl]-4-(tetrahydropyranyloxy)butan-1-ol

is used in the next reaction step without further purification.

2-(2-Methoxyphenyl)-1-phenyl-1-[4-(2-piperidin-1-ylethoxy)phenyl]-4-(tetrahydropyranyloxybutan-1-ol

is used in the next reaction step without further purification.

1-[3-(2-Dimethylaminoethoxy)phenyl]-1,2-diphenyl-4-(tetrahydropyranyloxy)butan-1-ol

is used in the next reaction step without further purification.

1-[4-(2-Benzyloxyethylsulfanyl)phenyl]-1,2-diphenyl-4-(tetrahydropyranyloxy)butan-1-ol

is used in the next reaction step without further purification.

1-[4-(2-Dimethylaminoethylsulfanyl)phenyl]-1,2-diphenyl-4-(tetrahydropyranyloxy)butan-1-ol

is used in the next reaction step without further purification.

f) Dehydration of the Triarylbutandiol Derivatives

(2-{4-[4-Benzyloxy-2-(4-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}ethyl)dimethylamine

4-Benzyloxy-2-(4-chlorophenyl)-1-[4-(2-dimethylaminoethoxy)phenyl]-1-phenylbutan-1-ol(10.7 g) is dissolved in methanol (70 ml) and concentrated hydrochloricacid is added to make the solution acidic. The mixture is stirred for4.5 h at room temperature and then at 50° C. for 1 h. The solvent isevaporated and the product is purified by flash chromatography (eluenttoluene:triethylamine 24:1). The yield is 5.6 g as a mixture of E- andZ-isomers (1:2).

¹H NMR (mixture of Z- and E-isomers, CDCl₃): 2.28 and 2.34 (2s, 6H),2.64 and 2.73 (2t, 2H), 2.78 and 2.83 (2t, 2H), 3.40 and 3.42 (2t, 2H),3.93 and 4.07 (2t, 2H), 4.36 and 4.38 (2s, 2H), 6.55-7.40 (m, 18H) fromwhich can be identified 6.58 and 6.75 (2d, 4H).

Using the same method the following compounds are prepared:

(2-{4-[4-Benzyloxy-2-(4-fluorophenyl)-1-phenylbut-1-enyl]phenoxy}ethyl)dimethylamine

¹H NMR (mixture of Z- and E-isomers, CDCl₃): 2.28 and 2.34 (2s, 6H),2.65 and 2.74 (2t, 2H), 2.78 and 2.83 (2t, 2H), 3.41 and 3.43 (2t, 2H),3.93 and 4.07 (2t, 2H), 4.37 and 4.39 (2s, 2H), 6.50-7,40 (m, 18H) fromwhich can be identified 6.58 and 6.75 (2d, 4H).

(2-{4-[4-Benzyloxy-2-(4-chlorophenyl)-1-(4-methoxyphenyl)but-1-enyl]phenoxy}ethyl)dimethylamine

¹H NMR (mixture of Z- and E-isomers, CDCl₃): 2.30 and 2.35 (2s, 6H),2.67 and 2.76 (2t, 2H), 2.81 (t, 2H), 3.41 (t, 2H), 3.69 and 3.81 (2s,3H), 4.38 (s, 2H), 6.56 and 6.86 (2d, 2H), 6.58 and 6.85 (2d, 2H), 6.75(d, 2H), 6.76 (d, 2H), 7.0-7.4 (m, 11H).

4-[4-(2-Benzyloxyethoxy)phenyl]-3-(4-chlorophenyl)-4-(4-methoxyphenyl)but-3-en-1-ol

is prepared according to the procedure of the example 1c. The Z- andE-isomers are separated by flash chromatography, eluent toluene:metanol99:1.

Z-isomer ¹H NMR (CDCl₃): 2.76 (t, 2H), 3.57 (br.t, 2H), 3.75 (dist.t,2H), 3.81 (s, 3H), 4.03 (dist.t, 2H), 4.59 (s, 2H), 6.59 (d, 2H), 6.76(d, 2H), 6.87 (d, 2H, 7.05 (d, 2H), 7.13 (d, 2H), 7.19 (d, 2H),7.27-7.40 (m, 5H); E-isomer ¹H NMR (CDCl₃): 2.76 (t, 2H), 3.58 (br.t,2H), 3.70 (s, 3H), 3.84 (dist.t, 2H), 4.17 (dist.t, 2H), 4.65 (s, 2H),6.57 (d, 2H), 6.77 (d, 2H), 6.90 (d, 2H), 7.06 (d, 2H), 7.15 (d, 2H),7.18 (d, 2H), 7.27-7.40 (m, 5H).

Using the same method the following compounds are prepared.

3-(3-Methoxyphenyl)-4-phenyl-4-[4-(2-piperidin-1-ylethoxy)phenyl]but-3-en-1-ol

Z-isomer: ¹H NMR (CDCl₃): 1.33-1.50 (m, 2H), 1.50-1.65 (m, 4H), 2.45(br.t., 4H), 2.67 (t, 2H), 2.73 (t, 2H), 3.58 (t, 2H), 3.65 (s, 3H),3.96 (t, 2H), 6.55 (d, 2H), 6.63-6.77 (m, 3H), 6.79 (d, 2H), 7.10 (t,1H), 7.20-7.40 (m, 5H); E-isomer: ¹H NMR (CDCl₃): 1.40-1.55 (m, 2H),1.55-1.70 (m, 4H), 2.51 (br.t., 4H), 2.77 (t, 2H), 2.80 (t, 2H), 3.61(s, 3H), 3.62 (t, 2H), 3.94 (t, 2H), 6.6-7.25 (m, 13H).

3-(2-Methoxyphenyl)-4-phenyl-4-[4-(2-piperidin-1-ylethoxy)phenyl]but-3-en-1-ol

Z-isomer: ¹H NMR (CDCl₃): 1.33-1.48 (m, 2H), 1.48-1.65 (m, 4H), 2.43(br.t., 4H), 2.20-2.50 (t, 2H), 2.65 (t, 2H), 3.43-3.60 (t, 2H), 3.62(s, 3H), 3.93 (t, 2H), 6.52 (d, 2H), 6.70-6.90 (m, 2H) under which 6.82(d, 2H), 7.05-7.43 (m, 7H); E-isomer: ¹H NMR (CDCl₃): 1.38-1.52 (m, 2H),1.52-1.70 (m, 4H), 2.51 (br.t., 4H), 2.38-2.58 (t, 2H), 2.77 (t, 2H),3.59 (s, 3H), 3.45-3.65 (m, 2H), 4.10 (t, 2H), 6.6-7.35 (m, 13H).

(E)-4-(3-Benzyloxyphenyl)-4-[4-(2-benzyloxyethoxy)phenyl]-3-phenyl-but-3-en-1-ol

¹H NMR (CDCl₃): 2.73 (t, 2H), 3.5-3.6 (m, 2H), 3.7-3.76 (m, 2H),4.0-4.03 (m, 2H), 4.60 (s, 2H), 5.05 (s, 2H), 6.56 (d, 2H), 6.78 (d,2H), 6.8-6.95 (m, 2H), 7.05-7.35 (m, 17H).

(Z)-4-[4-(2-Benzyloxyethylsulfanyl)phenyl]-3,4-diphenyl-but-3-en-1-ol

¹H NMR (CDCl₃): 2.75 (t, 2H), 3.02 (t, 2H), 3.56 (t, 4H), 4.47 (s, 2H),6.78 (d, 2H), 6.96 (d, 2H), 7.1-7.4 (m, 15H).

(Z)-4-[4-(2-Dimethylaminoethylsulfanyl)phenyl]-3,4-diphenyl-but-3-en-1-ol

MS: EI, m/e 403 (M⁺, 1%), 332 (1%), 72 (12%), 58 (100%).

g) Removal of the Protecting Benzyl Group

3-(4-Chlorolphenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]-4-phenylbut-3-en-1-ol

(2-{4-[4-Benzyloxy-2-(4-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}ethyl)dimethylamine(1.1 g, 2.1 mmol) is dissolved in toluene, Zn powder (0.4 g, 6.1 mmol)and acetyl chloride (0.6 g, 7.6 mmol) are added and the mixture isstirred at 40° C. for 3 h. Additional Zn (0.5 g) and acetyl chloride(0.6 g) are added and stirring is continued for another 5 h. Ethylacetate is added and the precipitate is filtered off. The solvents areevaporated and the residue is dissolved in methanol. The acetate esterof the product is hydrolyzed by making the mixture alkaline with 48%aqueous sodium hydroxide and stirring the mixture at room temperaturefor 2 h. Methanol is evaporated, the residue is dissolved in toluene andwashed with water. Toluene is evaporated and the isomers of the productare separated by flash chromatography. The yield of the Z-isomer is 0.25g and of the E-isomer 0.15 g.

Z-isomer: ¹H NMR (CDCl₃): 2.28 (s, 6H), 2.65 (t, 2H), 2.72 (t, 2H), 3.57(t, 2H), 3.94 (t, 2H), 6.58 (d, 2H), 6.76 (d, 2H), 7.07 (d, 2H), 7.15(d, 2H), 7.20-7.40 (m, 5H); E-isomer: ¹H NMR (CDCl₃): 2.34 (s, 6H), 2.74(t, 2H), 2.78 (t, 2H), 3.59 (t, 2H), 4.07 (t, 2H), 6.80-7.30 (m, 13H).

Using the same method the following compounds are prepared:

4-[4-(2-Dimethylaminoethoxy)phenyl]-3-(4-fluorophenyl)-4-phenylbut-3-en-1-ol

Z-isomer: ¹H NMR (CDCl₃): 2.27 (s, 6H), 2.64 (t, 2H), 2.72 (t, 2H), 3.56(t, 2H), 3.93 (t, 2H), 6.56 (d, 2H), 6.76 (d, 2H), 6.86 (t, 2H),7.00-7.40 (m, 7H); E-isomer: ¹H NMR (E-isomer, CDCl₃): 2.35 (s, 6H),2.75 (t, 2H), 2.78 (t, 2H), 3.60 (t, 2H), 4.08 (t, 2H), 6.75-7.40 (m,13H).

3-(4-Chlorophenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]-4-(4-methoxyphenyl)but-3-en-1-ol

Z-isomer: ¹H NMR (CDCl₃): 2.28 (s, 6H), 2.65 (t, 2H), 2.75 (t, 2H), 3.57(t, 2H), 3.81 (s, 3H), 3.94 (t, 2H), 6.58 (d, 2H), 6.75 (d, 2H), 6.87(d, 2H), 7.05 (d, 2H), 7.13 (d, 2H), 7.19 (d, 2H); E-isomer: ¹H NMR(CDCl₃): 2.33 (s, 6H), 2.74 (t, 2H), 2.75 (t, 2H), 3.56 (t, 2H), 3.69(s, 3H), 4.07 (t, 2H), 6.56 (d, 2H), 6.76 (d, 2H), 6.88 (d, 2H), 7.06(d, 2H), 7.17 (d, 2H).

h) Conversion of the Hydroxyl Group to Chlorine

(Z)-(2-{4-[4-Chloro-2-(4-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}ethyl)dimethylamine(No. 23)

(Z)-3-(4-Chlorophenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]-4-phenylbut-3-en-1-ol(0.22 g, 0.5 mmol) is dissolved in toluene. Thionyl chloride (0.2 g, 1.7mmol) is added and the mixture is refluxed for 45 min. Toluene is partlyevaporated and the precipitated hydrochloride salt of the product isfiltered. The yield is 0.2 g.

¹H NMR (HCl salt, CDCl₃): 2.88 and 2.90 (s, together 6H), 2.91 (t, 2H),3.40 (m, 4H), 4.40 (m, 2H), 6.58 (d, 2H), 6.81 (d, 2H), 7.07 (d, 2H),7.19 (d, 2H), 7.20-7.50 (m, 5H).

Using the same method the following compounds are prepared:

(E)-(2-{4-[4-Chloro-2-(4-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}ethyldimethylamine (No. 24)

¹H NMR (HCl salt, CDCl₃): 2.35-3.02 (m, 2H), 2.95 (s, 6H), 3.35-3.55 (m,4H), 4.46-4.60 (m, 2H), 6.75-7.30 (m, 13H).

(Z)-(2-4-[4-Chloro-2-(4-fluorophenyl)-1-phenylbut-1-enyl]phenoxy}ethyl)dimethylamine(No. 25)

¹H NMR (HCl salt, CDCl₃): 2.88 (s, 6H), 2.94 (t, 2H), 3.41 (m, 4H), 4.39(m, 2H), 6.56 (d, 2H), 6.80 (d, 2H), 6.91 (t, 2H), 7.10 (dd, 2H),7.20-7.40 (m, 5H).

2-{4-[4-Chloro-2-(4-chlorophenyl)-1-(4-methoxyphenyl)but-1-enyl]phenoxy}ethyl)dimethylamine(No. 26 and 27)

Z-isomer (No. 26): ¹H NMR (HCl salt, CDCl₃+MeOH-d₄): 2.89 (s, 6H), 2.94(t, 2H), 3.41 (m, 4H), 3.84 (s, 3H), 4.34 (m, 2H), 6.59 (d, 2H), 6.81(d, 2H), 6.90 (d, 2H), 7.06 (d, 2H), 7.18 (d, 2H), 7.19 (d, 2H);E-isomer (No. 27): ¹H NMR (HCl salt, CDCl₃+MeOH-d₄): 2.91 (t, 2H), 2.98(s, 6H), 3.41 (t, H), 3.54 (m, 2H), 3.71 (s, 3H), 4.45 (m, 2H), 6.59 (d,2H), 6.77 (d, 2H), 6.94 (d, 2H), 7.06 (d, 2H), 7.17-7.18 (d, 2H), 7.23(d, 2H).

1-(2-{4-[4-Chloro-2-(3-methoxyphenyl)-1-phenylbut-1-enyl]phenoxy}ethyl)piperidine(No. 28 and 29)

Z-isomer (No. 28): ¹H NMR (HCl salt, MeOH-d₄): 1.45-2.10 (m, 6H), 2.92(t, 2H), 3.06 (dt, 2H), 3.44 (t, 2H), 3.47-3.66 (m, 4H), 3.68 (s, 3H),4.27 (dist.t., 2H), 6.70-6.85 (m, 5H), 6.92 (d, 2H), 7.15 (dt, 1H),7.30-7.50 (m, 5H); E-isomer (No. 29): ¹H NMR (HCl salt, MeOH-d₄):1.45-2.15 (m, 6H), 2.96 (t, 2H), 3.12 (dt, 2H), 3.47 (t, 2H), 3.58-3.75(m, 4H), 3.62 (s, 3H), 4.44 (dist.t., 2H), 6.65-6.83 (m, 3H), 6.90-6.97(m, 2H), 7.01-7.18 (m, 6H), 7.31 (d, 2H).

1-(2-{4-[4-Chloro-2-(2-methoxyphenyl)-1-phenylbut-1-enyl]phenoxy}ethyl)piperidine(No. 30 and 31)

Z-isomer (No. 30): ¹H NMR (HCl salt, MeOH-d₄): 1.50-2.05 (m, 6H), 2.88(t, 2H), 3.05 (dt, 2H), 3.41 (t, 2H), 3.45-3.65 (m, 4H), 3.86 (s, 3H),4.25 (dist.t., 2H), 6.65-6.79 (m, 3H), 6.88-7.00 (m, 4H), 7.20 (dt, 1H),7.30-7.50 (m, 5H); E-isomer (No. 31): ¹H NMR (HCl salt, MeOH-d₄):1.55-2.20 (m, 6H), 2.92 (t, 2H), 3.13 (dt, 2H), 3.43 (t, 2H), 3.58-3.75(m, 4H), 3.84 (s, 3H), 4.45 (dist.t., 2H), 6.73 (dt, 1H), 6.89-7.30 (m,7H), 7.08 (d, 2H), 7.18 (dt, 1H), 7.32 (d, 2H).

(Z)-1-[4-(2-Benzyloxyethylsulfanyl)phenyl]-1,2-diphenyl-4-chloro-but-1-ene

¹H NMR (CDCl₃): 2.92 (t, 2H), 3.02 (t, 2H), 3.41 (t, 2H), 3.56 (t, 2H),4.47 (s, 2H), 6.78 (d, 2H), 6.96 (d, 2H), 7.10-7.40 (m, 15H).

(Z)-1-[4-(2-Dimethylaminoethylsulfanyl)phenyl]-1,2-diphenyl-4-chloro-but-1-ene(No. 32)

¹H NMR (CDCl₃): 2.28 (s, 6H), 2.46 (dist. t, 2H), 2.85-2.95 (m, 4H),3.41 (dist. t, 2H), 6.79 (d, 2H), 6.96 (d, 2H), 7.00-7.40 (m, 10H).

1-[4-(2-Benzyloxyethoxy)phenyl]-4-chloro-2-(4-chlorophenyl)-1-(4-methoxyphenyl)but-1-ene

Z-isomer, ¹H NMR (CDCl₃): 2.93 (t, 2H), 3.41 (t, 2H), 3.83 (s, 2H), 3.76(dist.t, H), 4.04 (dist.t, 2H), 4.59 (s, 2H), 6.59 (d, 2H), 6.77 (d,2H), 6.87 (d, 2H), 7.05 (d, 2H), 7.15 (d, 2H), 7.19 (d, 2H), 7.27-7.40(m, 5H); E-isomer ¹H NMR (CDCl₃): 2.93 (t, 2H), 3.41 (t, 2H), 3.70 (s,3H), 3.85 (dist.t, 2H), 4.18 (dist.t, 2H), 4.65 (s, 2H), 6.57 (d, 2H),6.79 (d, 2H), 6.92 (2H), 7.06 (d, 2H), 7.16 (d, 2H), 7.18 (d, 2H),7.27-7.40 (m, 5H).

(E)-1-(3-Benzyloxyphenyl)-1-[4-(2-benzyloxyethoxy)phenyl]-4-chloro-3-phenyl-but-1-ene

The compound is prepared by using the method described in the examples1d using Ph₃P and CCl₄ as reagents.

¹H NMR (CDCl₃): 2.93 (t, 2H), 3.40 (t, 2H), 3.71-3.76 (m, 2H), 3.98-4.05(m, 2H), 4.58 (s, 2H), 5.06 (s, 2H), 6.60 (d, 2H), 6.78 (d, 2H),6.85-7.50 (m, 19H).

(Z)-{2-[3-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]ethyl}dimethylamine(No. 33)

1-[3-(2-Dimethylaminoethoxy)phenyl]-1,2-diphenyl-4-(tetrahydropyranyloxy)butan-1-ol(0.93 g, 1,9 mmol) is dissolved in toluene (10 ml). Triethylamine (1.9mmol) is added to the solution and the mixture is cooled to −10° C.Thionyl chloride (5.8 mmol) is added to the mixture at −10-±0° C. Themixture was stirred for 1 hour at 0-5° C., warmed up to 80° C. andstirred at this temperature for 3 hours. Solvent was evaporated, theresidue was dissolved to toluene, washed with 2 N NaOH and with water.The Z-isomer of the product was crystallized from ethyl acetate as HClsalt. Yield 0.15 g

¹H NMR (HCl salt, CDCl₃): 2.79 (s, 6H), 2.94 (t, 2H), 3.20-3.29 (m, 2H),3.42 (t, 2H), 4.12-4.20 (m, 2H), 6.40 (s, 1H), 6.51-6.62 (m, 2H), 6.98(t, 1H), 7.10-7.45 (m, 10H).

i) Removal of the Protecting Groups

(E)-3-{4-Chloro-1-[4-(2-hydroxyethoxyphenyl]-2-phenyl-but-1-enyl}-phenol(No. 34)

(E)-4-(3-Benzyloxyphenyl)-4-[4-(2-benzyloxyethoxy)phenyl]-4-chloro-3-phenyl-but-1-ene(1.95 g, 3.39 mmol) is hydrogenated in ethanol-ethyl acetate (5 ml:20ml) containing triethylamine (3.4 mmol) and 10% palladium on carbon(0.195 g) as a catalyst. The catalyst is filtered off and the solvent isevaporated. The product is purified with flash chromatography andcrystallized from toluene- methanol (9:1). Yield 0.23 g.

¹H NMR (CDCl₃+MeOH-d₄): 2.95 (t, 2H), 3.42 (t, 2H), 3.8-4.0 (m, 4H),6.56 (d, 2H), 6.75-6.82 (m, 4H), 7.10-7.25 (m, 7H).

Using the same method the following compound included in the inventionis prepared:

(Z)-3-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]propan-1-ol (No. 35)

¹H NMR (CDCl₃): 1.96 (quint., 2H), 2.92 (t, 2H), 3.42 (t, 2H), 3.80 (q,2H), 3.98 (t, 2H), 6.55 (d, 2H), 6.78 (d, 2H), 7.11-7.40 (m, 10H).

(Z)-2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenylsulfanyl]ethanol (No.36)

is prepared according to the procedure of the example 2g.

¹H NMR (CDCl₃): 2.93 (t, 2H), 3.00 (t, 2H), 3.41 (t, 2H), 3.64 (t, 2H),6.81 (d, 2H), 7.01 (d, 2H), 7.10-7.40 (m, 10H).

Using the same method the following compound included in the inventionis prepared.

(Z)-2-{4-[4-Chloro-2-(4-chlorophenyl)-1-(4-methoxyphenyl)but-1-enyl]phenoxy}ethanol(No. 37)

¹H NMR (CDCl₃): 2.94 (t, 2H), 3.41 (t, 2H), 3.83 (s, 3H), 3.85-4.00 (m,4H), 6.59 (d, 2H), 6.78 (d, 2H), 6.90 (d, 2H), 7.06 (d, 2H), 7.16 (d,2H), 7.19 (d, 2H).

Example 5 a) 1-[4-(2-Chloroethoxy)phenyl]-2-(2-chlorophenyl)ethanone

1-[4-(2-Chloroethoxy)phenyl]-2-(2-chlorophenyl)ethanone is preparedaccording to the method described in the example 4a using2-chloroethoxybenzene and 2-chlorophenylacetic acid as startingmaterials.

¹H NMR (CDCl₃): 3.85 (t, 2H), 4.30 (t, 2H), 4.39 (s, 2H), 6.98 (d, 2H),7.22-7.26 (m, 3H), 7.39-7.50 (m, 1H), 8.04 (d, 2H).

Using the same method the following compound is prepared:

1-[4-(2-Chloroethoxy)phenyl]-2-phenylethanone

¹H NMR (CDCl₃): 3.83 (t, 214), 4.24 (s, 214), 4.28 (t, 214), 6.94 (d,214), 7.2-7.4 (m, 5H), 8.00 (d, 2).

b) 2-(2-Chlorophenyl)-1-[4-(2-piperidinylethoxy)phenyl]ethanone

The mixture of 1-[4-(2-chloroethoxy)phenyl]-2-(2-chlorophenyl)ethanone(4 g, 13 mmol) and piperidine (5.8 g, 68 mmol) in 80% aqueous acetone(50 ml) is refluxed for 12 h. Additional portions of 0.3 g of piperidineare added three times in 4 h intervals to the mixture. The solvents areevaporated. Diethyl ether is added and the precipitated piperidinehydrochloride is filtered off. Diethyl ether is evaporated and theresidual product is purified by flash chromatography (eluenttoluenetriethylamine 9:1). The yield is 4.1 g, 89%.

¹H NMR (CDCl₃): 1.38-1.56 (m, 2H), 1.56-1.68 (m, 4H), 2.45-2.62 (m, 4H),2.79 (t, 2H), 4.17 (t, 2H), 4.38 (s, 2H), 6.96 (d, 2H), 7.19-7.25 and3.37-7.44 (2m, together 4H), 8.01 (d, 2H).

1-[4-(2-Imidazol-1-yl-ethoxy)phenyl]-2-phenylethanone

is prepared from 1-[4-(2-chloroethoxy)phenyl]-2-phenylethanone andimidazole in DMF using sodium hydride as a base according to theprocedure described in the example 1a.

¹H NMR (CDCl₃): 4.22 (s, 2H), 4.20-4.37 (m, 4H), 6.88 (d, 2H), 7.03 (s,1H), 7.07 (s, 1H), 7.20-7.37 (m, 5H), 7.60 (s, 1H), 7.97 (d, 2H).

c)2-(2-Chlorophenyl-1-[4-(2-piperidinylethoxy)phenyl]-4-(tetrahydropyranyloxy)butan-1-one

2-(2-Chlorophenyl-1-[4-(2-piperidinylethoxy)phenyl]-4-(tetrahydropyranyloxy)butan-1-oneis prepared by PTC reaction according to the method described in theexample 4d using2-(2-chlorophenyl)-1-[4-(2-piperidinylethoxy)phenyl]ethanone (1.5 g, 4.2mmol) and 2-tetrahydropyranyloxy-1-iodoethane (1.3 g, 5.1 mmol) as thestarting materials. The product (1.6 g) is used for the followingreaction step without further purification.

¹H NMR (CDCl₃): from the complex spectrum can be identified 2.40-2.60(m, 4H), 2.75 (t, 2H), 4.12 (t, 2H), 4.50-4.62 (m, 1H), 5.24-5.36 (m,1H), 6.87 (d, 2H), 7.10-7.25 and 3.37-7.44 (2m, together 4H), 7.98 (d,2H).

Using the same method the following compound is prepared.

1-[4-(2-Imidazol-1-yl-ethoxy)phenyl]-2-phenyl-4-(tetrahydro-pyranyloxy)butan-1-one

¹H NMR (CDCl₃): 1.4-1.9 (m, 6H), 1.95-2.2 (m, 1H), 2.4-2.60 (m, 1H),3.2-3.9 (m, 4H), 4.2-4.37 (m, 4H), 4.45-4.55 (m, 1H), 4.79 (dt, 1H),6.80 (dd, 2H), 6.99 (s, 1H), 7.05 (s, 1H), 7.15-7.3 (m, 5H), 7.55 (s,1H), 7.95 (d, 2H).

d)2-(2-Chlorophenyl-1-phenyl-1-[4-(2-piperidinylethoxy)phenyl]-4-(tetrahydro-pyranyloxy)butan-1-ol

is prepared according to the procedure described in the example 4e. Theproduct is used in the following reaction step without furtherpurification.

Using the same method the following compounds are prepared:

1-[4-(2-Imidazol-1-yl-ethoxy)phenyl]-2-phenyl-4-(tetrahydro-pyranyloxy)-1-[3-(tetrahydro-pyranyloxy)phenyl]-butan-1-ol

The compound is used in the next reaction step without furtherpurification.

e)3-(2-Chlorophenyl)-4-phenyl-4-[4-(2-piperidin-1-ylethoxy)phenyl]but-3-en-1-ol

2-(2-Chlorophenyl-1-phenyl-1-[4-(2-piperidinylethoxy)phenyl]-4-(tetrahydro-pyranyloxy)butan-1-olis dehydrated according to the procedure described in the example 1c.The Z-isomer of the product is purified by flash chromatography (eluenttoluene-triethylamine 13:1)

Z-isomer: ¹H NMR (CDCl₃): 1.35-1.48 (m, 2H), 1.48-1.68 (m, 4H),2.38-2.48 (m, 4H), 2.66 (t, 2H), 2.58-2.87 (m, 2H), 3.47-3.67 (m, 2H),3.94 (t, 2H), 6.54 (d, 2H), 6.84 (d, 2H), 7.07-7.41 (m, 9H).

Using the same method the following compound is prepared.

3-{4-Hydroxy-1-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenyl-but-1-enyl}-phenol

E-isomer: ¹H NMR (CDCl₃+MeOH-d₄): 2.83 (t, 2H), 3.60 (t, 2H), 4.11(dist. t, 2H), 4.20 (t, 2H), 6.48 (d, 2H), 6.76 (d, 2H), 6.66-6.9 (m,4H), 6.92 (s, 1H), 698 (s, 1H), 7.08-7.32 (m, 5H), 7.36 (s, 1H);Z-isomer: ¹H NMR (CDCl₃+MeOH-d₄): 2.73 (t, 2H), 3.54 (t, 2H), 4.23-4.4(m, 4H), 6.35-7.23 (m, 15H), 7.55 (s, 1H).

f)(Z)-1-(2-{4-[4-Chloro-2-(2-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}ethyl)piperidine(No. 38)

is prepared according to the procedure described in the example 1d.

¹H NMR (CDCl₃): 1.33-1.49 (m, 2H), 1.49-1.68 (m, 4H), 2.40-2.50 (m, 4H),2.67 (t, 2H), 2.80-3.50 (m, 2H), 3.25-3.56 (m, 2H), 3.95 (t, 2H), 6.54(d, 2H), 6.85 (d, 2H), 7.06-7.43 (m, 9H).

Using the same method the following compound included in the inventionis prepared.

3-{4-Chloro-1-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenyl-but-1-enyl}phenol(No. 39 and 40)

E-isomer (No. 39): ¹H NMR (CDCl₃): 2.94 (t, 2H), 3.41 (t, 2H), 4.07(dist. t, 2H), 4.25 (t, 2H), 6.50 (d, 2H), 6.79 (d, 2H), 6.70-6.81 (m,2H), 6.98 (s, 2H), 7.10-7.24 (m, 7H), 7.51 (s, 1H); Z-isomer (No. 40):¹H NMR (CDCl₃+MeOH-d₄, HCl-salt): 2.90 (dist.t, 2H), 3.40 (dist.t, 2H),4.33 (dist. t, 2H), 4.65 (dist.t, 2H), 6.35-7.25 (m, 13H), 7.38 (s, 1H),7.48 (s, 1H), 9.20 (s, 1H).

Example 6 a) (4-Amino-phenyl)phenyl-methanone

4-Nitrobenzophenone (5.0 g, 0.022 mol) is dissolved inethanol-dichloromethane (40 ml:30 ml) and hydrogenated at roomtemperature with 10% palladium on carbon (0.5 g) as a catalyst. Thecatalyst is filtered off and the filtrate is evaporated to dryness. Theproduct is used in the next reaction step without further purification.Yield 5.2 g.

¹H NMR (CDCl₃): 6.67 (d, 2H), 7.4-7.6 (m, 3H), 7.7-7.6 (m, 4H).

b) McMurry Reaction

4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenylamine

Zinc (10.0 g, 0.154 mol) and tetrahydrofuran (THF) (120 ml) is added tothe reaction vessel and cooled to −10° C. To the mixture is addeddropwise titan tetrachloride (14.4 g, 0.076 mol) at about −10° C. Afterthe addition is completed the mixture is refluxed for two hours. Then itis cooled to 40° C. and (4-Aminophenyl)phenyl-methanone (5.1 g, 0.0258mol) and 3-chloropropiophenone (4.36 g, 0.0258 mol) are dissolved in THF(50 ml) and added to the mixture. Refluxing is continued for additional3.5 hours. The cooled reaction mixture is poured in aqueous potassiumcarbonate solution (14 g K₂CO₃+140 ml water) and allowed to stand overnight. The mixture is filtered and the precipitate is washed three timeswith THF. The filtrate is evaporated to dryness. The residue isdissolved in ethyl acetate and washed with water. Yield 9.6 g Z-isomerbeing the only isomer.

Z-isomer: ¹H NMR (CDCl₃): 2.90 (t, 2H), 3.41 (t, 2H), 6.32 (d, 2H), 6.64(d, 2H), 7.0-7.4 (m, 10H).

Using the same method the following compound included in the inventionis prepared.

N-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenyl]-N′,N′-dimethylethane-1,2-diamine(No. 47)

starting from [4-(2-dimethylaminoethylamino)phenyl]phenyl methanone(preparation described in U.S. Pat. No. 5,693,674) and3-chloropropiophenone.

Z-isomer: ¹H NMR (as HCl-salt, MeOH-d₄): 2.95 (s, 6H), 2.99 (t, 2H),3.44 (t, 2H), 3.47 (t, 2H), 3.68 (t, 2H), 6.90-7.10 (m, 4H), 7.15-7.40(m, 10H).

c) (Z)-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenylamino]acetic AcidEthyl Ester

(Z)-4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenylamine (2.0 g, 5.99 mmol),ethanol (30 ml), ethyl bromoacetate (2.5 g, 15 mmol) and sodium acetate(2.4 g, 17.9 mmol) are added to the reaction vessel and refluxed forthree hours. Then the solvent is evaporated and the residue is dissolvedin water and ethyl acetate. Ethyl acetate phase is dried and evaporatedto dryness. Yield 2.9 g.

¹H NMR (CDCl₃): 1.26 (t, 3H), 2.90 (t, 2H), 3.41 (t, 2H), 4.20 (q, 2H),6.25 (d, 2H), 6.68 (d, 2H), 7.10-7.40 (m, 10H).

d) (Z)-2-F4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenylamino]ethanol (No.41)

(Z)-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenylamino]acetic acid ethylester (2.9 g, 6.9 mmol) is dissolved in tetrahydrofuran and lithiumaluminum hydride (0.34 g, 8.97 mmol) is added in small portions duringfifteen minutes. The mixture is stirred at room temperature for twohours. Then the solvent is evaporated to dryness and the residue isdissolved in ethyl acetate and washed with water. Ethyl acetate phase isevaporated to dryness and the product is purified by flashchromatography with toluene:methanol:triethylamine solution (10:0.3:0.3)as an eluent. Yield 0.47 g.

¹H NMR (CDCl₃): 2.89 (t, 2H), 3.17 (t, 2H), 3.41 (t, 2H), 3.73 (t, 2H),6.29 (d, 2H), 6.67 (d, 2H), 7.10-7.40 (m, 10H).

Example 7 a)4-{2-[4-(2-Benzyloxyethoxy)phenyl]-1-(2-chloroethyl)-2-phenylvinyl}phenol

is prepared according to the method of example 6b using[(4-benzyloxyethoxy)phenyl]phenylmethanone and3-chloro-1-(4-hydroxyphenyl)propan-1-one as starting materials. Theproduct is mixture of Z- and E-isomers.

¹H NMR (CDCl₃): 2.88 and 2.93 (2t, 2H), 3.42 and 3.43 (2t, 2H), 3.74 and3.84 (2dist.t, 2H), 4.01 and 4.16 (2dist.t, 2H), 4.58 and 4.65 (2s, 2H),6.55-7.40 (m, 18H).

b)4-{1-(2-Chloroethyl)-2-(4-(2-hydroxyethoxy)phenyl]-2-phenylvinyl}phenol(No. 42 and 43)

is prepared according to the procedure of the example 1e. The isomersare purified by flash chromatography (eluentdichloromethane-methanol-triethylamine 98:2:1)

Z-isomer (No. 42): ¹H NMR (CDCl₃): 2.87 (t, 2H), 3.43 (t, 2H), 3.83-3.90(m, 2H), 3.90-3.97 (m, 2H), 6.56 (d, 2H), 6.66 (d, 2H), 6.80 (d, 2H),6.96 (d, 2H), 7.20-7.40 (m, 5H); E-isomer (No. 43): ¹H NMR (CDCl₃): 2.92(t, 2H), 3.38 (t, 2H), 3.90-4.02 (m, 2H), 4.03-4.14 (m, 2H), 6.63 (d,2H), 6.89 (d, 2H), 6.95 (d, 2H), 7.20 (d, 2H), 6.85-7.17 (m, 5H).

Example 8

{2-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]ethyl}methylprop-2-ynylamine(No. 44) is prepared according to example 1a starting fromZ-4-chloro-1,2-diphenyl-1[4-[2-(N-methylamino)ethoxy]-phenyl]-1-butene(preparation described in U.S. Pat. No. 5,491173) and propargyl bromide.

¹H NMR (citrate salt, MeOH-d₄): 2.74 (s, 3H), 2.82 and 2.86 (2s, 4H),2.93 (t, 2H), 3.06 (t, 1H), 3.29 (dist. t, 2H), 3.44 (t, 2H), 3.85 (d,2H), 4.16 (dist. t, 2H), 6.68 (d, 2H), 6.86 (d, 2H), 7.15-7.47 (m, 10H).

Example 9 a) (Z)-[4-(4-Hydroxy-1,2-diphenylbut-1-enyl)phenyloxy]aceticAcid Ethyl Ester

is prepared from (Z)-(4-hydroxy-1,2-diphenylbut-1-enyl)phenol(preparation described in U.S. Pat. No. 4.996.225) and ethylbromoacetate according to the procedure described in the example 1ausing NaH as a base.

¹H NMR (CDCl₃): 1.25 (t, 3H), 2.74 (t, 2H), 3.57 (t, 2H), 4.23 (q, 2H),4.47 (s, 2H), 6.56 (d, 2H), 6.79 (d, 2H), 7.10-7.45 (m, 10H).

(Z)-2-[4-(4-Hydroxy-1,2-diphenylbut-1-enyl)phenoxy]butyric Acid EthylEster

is prepared according to the same procedure using ethyl 2-bromobutyrateas a alkylating reagent.

¹H NMR (MeOH-d₄): 0.98 (t, 3H), 1.17 (t, 3H), 1.86 (m, 2H), 2.70 (t,2H), 3.47 (t, 2H), 4.12 (m, 2H), 4.50 (dd, 1H), 6.50 (d, 2H), 6.76 (d,2H), 7.0-7.4 (m, 10H).

b) (Z)-[4-(4-Chloro-1,2-diphenylbut-1-enyl]phenoxy)acetic Acid EthylEster

is prepared according to procedure described in the example 1d usingPh₃P and CCl₄ as reagents.

¹H NMR (CDCl₃): 1.25 (t, 3H), 2.92 (t, 2H), 3.41 (t, 2H), 4.23 (q, 2H),4.50 (s, 2H), 6.55.(d, 2H), 6.80 (d, 2H), 7.10-7.45 (m, 10H).

Using the same method the following compound is prepared.

(Z)-2-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]butyric Acid EthylEster

¹H NMR (MeOH-d₄): 1.01 (t, 3H), 1.16 (t, 3H), 1.89 (m, 2H), 2.91 (t,2H), 3.40 (t, 2H), 4.15 (m, 2H), 4.40 (dd, 1H), 6.52 (d, 2H), 6.76 (d,2H), 7.0-7.4 (m, 10H).

c) (Z)-3-[4-(4-Chloro-1.2-diphenylbut-1-enyl)phenoxymethyl]pentan-3-ol(No. 45)

Grignard reagent is prepared from Mg turnings (0.29 g, 12 mmol) andbromoethane (1.25 g, 12 mmol) in tetrahydrofuran (4 ml).(Z)-[4-(4-Chloro-1,2-diphenyl-but-1-enyl]phenoxy)acetic acid ethyl ester(1.0 g, 23 mmol, from example 9b) in tetrahydrofuran (11 ml) is added inroom temperature and the reaction mixture is refluxed for 2 h. Saturatedammonium chloride is added and tetrahydrofuran is evaporated. Theproduct is extracted into ethyl acetate. The organic layer is dried andevaporated to dryness. The yield is 1.0 g.

¹H NMR (CDCl₃): 0.87 (t, 6H), 1.58 (q, 414), 2.92 (t, 2H), 3.42 (t, 2H),3.68 (s, 2H), 6.56 (d, 2H), 6.78 (d, 2H), 7.10-7.45 (m, 10H).

Example 10

(Z)-2-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]butan-1-ol (No. 46)

Z-2-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]butyric acid ethyl ester(0.98 g, 2.2 mmol) is reduced by lithium aluminum hydride (0.041 g, 1.1mmol) in tetrahydrofuran. Ice-water is added and tetrahydrofuran isevaporated. The product is extracted into ethyl acetate, dried and thesolvent is evaporated. Yield 0.55 g.

¹H NMR (CDCl₃): 0.89 (t, 3H), 1.54-1.70 (m, 2H), 2.91 (t, 2H), 3.58-3.76(m, 2H), 4.10-4.20 (m, 1H), 6.57 (d, 2H), 6.77 (d, 2H), 7.10-7.40 (m,10H).

Example 11

E-3-(4-Chloro-1-{4-[2-(2-hydroxyethoxy)ethoxy]phenyl}-2-phenylbut-1-enyl)phenol

a) 1-{4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl}-2-phenylethanone

is prepared according to example 4c starting from1-(4-hydroxyphenyl)-2-phenyl ethanone (prepared according examples 4a-b)(10.0 g, 47.1 mmol) and 2-(2-benzyloxyethoxy)ethyl chloride (11.0 g,51.8 mmol). The product was triturated three times with warm heptane toremove byproducts. Yield 9.6 g, 52%.

¹H NMR (CDCl₃): 3.60-3.79 (m, 4H), 3.85 (dist. t, 2H), 4.16 (dist. t,2H), 4.20 (s, 2H), 4.56 (s, 2H), 6.92 (d, 2H), 7.20-7.41 (m, 10H), 7.96(d, 2H).

b)1-{4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl}-2-phenyl-4-(tetrahydropyran-2-yloxy)butan-1-one

is prepared by using the method described in the example 4d startingfrom 1-{4-[2-(2-benzyloxyethoxy)ethoxy]phenyl}-2-phenylethanone (8.4g,21.5 mmol) and 2-(tetrahydropyran-2-yloxy)ethyl iodide (6.6 g, 25.8mmol). The product (11.7 g) is used in the next reaction step withoutfurther purification.

¹H NMR (CDCl₃): 1.401.95 (m, 6H), 2.00-2.20 and 2.40-2.60 (2m, together2H), 3.60-3.80 (m, 8H), 3.83 (dist.t, 2H), 4.13 (dist.t, 2H), 4.45-4.55(m, 1H), 4.55 (s, 2H), 4.80 (t, 1H), 6.86 (d, 2H), 7.14-7.39 (m, 10H),7.96 (d, 2H).

c)1-{4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl}-2-phenyl-4-(tetrahydropyran-2-yloxy)-1-[3-(tetrahydropyran-2-yloxy)phenyl]butan-1-ol

is prepared by using the method described in the example 4e startingfrom1-{4-[2-(2-benzyloxyethoxy)ethoxy]phenyl}-2-phenyl-4-(tetrahydropyran-2-yloxy)butan-1-one(10 g, 19.2 mmol) and 3-(tetrahydropyran-2-yloxy)phenyl bromide (9.8 g,38 mmol). The product is purified by flash chromatography withtoluene-methanol (50:1) as eluent. Yield 5.7 g, 43%.

¹NMR (CDCl₃): 1.40-2.20 (m, 10H), 3.5-4.1 (m, 14H), 4.30-4.50 (2m, 1H),4.52 (s, 1H), 4.53 (s, 1H), 6.60 (d, 2H), 6.90-7.40 (m, 16H).

d)Z,E-3-(1-{4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl}-4-hydroxy-2-phenylbut-1-enyl)phenol

is prepared from1-{4-[2-(2-benzyloxyethoxy)ethoxy]phenyl}-2-phenyl-4-(tetrahydropyran-2-yloxy)-1-[3-(tetrahydropyran-2-yloxy)phenyl]butan-1-ol(5.7 g, 8.2 mmol) by using the method described in the example 1c exceptthat toluene is used instead of acetic anhydride (30 ml) andtriethylamine (0.91 g, 0.9 mmol) is added. The product (3.8 g) is usedin the next reaction step without further purification.

¹H NMR (CDCl₃): 2.78 (t, 2H), 3.55-4.20 (m, 10H), 4.55 and 4.58 (2s,2H), 6.56 (d, 2H), 6.73-6.93 (m, 3H), 7.1-7.4 (m, 13H).

e)Z,E-3-(1-{4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl}-4-chloro-2-phenylbut-1-enyl)phenol

is prepared fromZ,E-3-(1-{4-[2-(2-benzyloxyethoxy)ethoxy]phenyl}-4-hydroxy-2-phenylbut-1-enyl)phenol(3.8 g, 7.4 mmol) by using the method described in example 4h exceptthat triethylamine (1.64 g, 16.2 mmol) is added to the reaction mixture.The product is purified by flash chromatography. Yield 2.5 g.

¹H NMR (CDCl₃): 2.92 (t, 2H), 3.40 (t, 2H), 3.58-4.17 (m, 8H) 4.53 and4.57 (2s, 2H), 6.53 (d, 2H), 6.71-6.9 (m, 6H), 7.1-7.4 (m, 10H).

f)E-3-(4-Chloro-1-{4-[2-(2-hydroxyethoxy)ethoxy]phenyl}-2-phenylbut-1-enyl)phenol

Z,E-3-(1-{4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl}-4-chloro-2-phenylbut-1-enyl)phenol(2.0 g, 3.78 mmol) is dissolved in ethyl acetate (30 ml). Zn (0.062 g,0.95 mmol) and acetyl chloride (0.74 g, 9.5 mmol) are added undernitrogen atmosphere. The mixture is stirred at 50° C. for 3 h. Themixture is filtered and the solvent is evaporated. The residue isdissolved in 80% aqueous methanol containing 3% of sodium hydroxide. Themixture is stirred at room temperature for 2 h and methanol isevaporated. Water (5 ml) is added and the product is extracted intoethyl acetate (10 ml). The mixture is dried and the solvent isevaporated. The product is purified first by flash chromatography(eluent toluene:methanol 9:1) and then crystallized from toluene andrecrystallized from toluene-acetone. Yield 0.15 g.

¹H NMR (CDCl₃): 2.94 (t, 2H), 3.41 (t, 2H), 3.59-3.63 (m, 2H), 3.67-3.72(m, 2H), 3.78 (dist.t, 2H), 4.01 (dist.t, 2H), 6.56 (d, 2H), 6.78 (d,2H), 6.70-6.90 (m, 3H), 7.1-7.3 (m, 6H).

Those skilled in the art will recognize that while specific embodimentshave been illustrated and described, various modifications and changesmay be made without departing from the spirit and scope of theinvention.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims. Allpublications, patent applications and patents cited herein are fullyincorporated by reference.

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Henderson V W: Estrogen, cognition, and a woman's risk of Alzheimer'sdisease. Am J Med 103(3A):11S-18S, 1997.

Kangas L, Gronroos M, Nieminen A-L; Bioluminescence of cellular ATP: Anew method for evaluating cytotoxic agents in vitro. Medical Biol 65:338-343, 1984.

Kangas L, Nieminen A-L, Blanco G, Grönroos M, Kallio S, Karjalainen A,Perilä M, Sö2152 dervall M, Toivola R: A new triphenylethylene compound,Fc-1157a. II. Antitumor effect. Cancer Chemother Pharmacol 17: 109-113,1986.

Khovidhunkit W, Shoback D M: Clinical effects of raloxifenehydrochloride in women. Ann Intern Med 130(5): 431-439, 1999.

Lobo R A: Benefits and risks of estrogen replacement therapy. Am JObstet Gynecol 173:982-990, 1995.

Macgregor J I, Jordan V C: Basic guide to the mechanism of antiestrogenaction. Pharmacol Rev 50:151-196, 1998.

Peng Z, Tuukkanen J, Zhang H, Jämsä T, Väänänen K: The mechanicalstrength of bone in different rat models of experimental osteoporosis.Bone 15: 523-532, 1994.

Terenius L: Structure-activity relationship of anti-oestrogens withregard to interaction with 17β-oestradiol in the mouse uterus andvagina. Acta Endocrinol 66: 431-447, 1971.

What is claimed is:
 1. A compound of the formula:

wherein R1 is H, halogen, OCH₃, or OH; R2 is selected from the groupconsisting of

—Y—(CH₂)_(n)CH₂—O—R6, 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy,2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy,and carboxymethoxy; where X is NH or S; n is an integer from 1 to 4; R4and R5, which are the same or different, are a 1 to 4 carbon alkyl, H,—CH₂C≡CH or —CH₂CH₂OH; or R4 and R5 form an N-containing five- orsix-membered ring or heteroaromatic ring selected from the groupconsisting of an imidazole ring and a piperidine ring; Y is O, NH or S;and R6 is H, —CH₂CH₂OH, or —CH₂CH₂Cl; and R3 is H, halogen, OH or —OCH₃;or a stereoisomer; or a non-toxic pharmaceutically acceptable salt orester thereof or mixtures thereof, provided that when R2 is —O—CH₂CH₂—OHor —O—CH₂COOH in the 4-position of the phenyl, then R1 and R3, cannotsimultaneously be H, or OH in the 4-position of the phenyl; and if R1 isOH in the 4-position of the phenyl, R3 cannot be H.
 2. A compoundaccording to claim 1, wherein R1 is H, halogen, OCH₃, or OH; and R2 is

where X is NH or S; and n is an integer from 1 to 4; and R4 and R5,which are the same or different, are a 1 to 4 carbon alkyl, H, —CH₂C≡CHor —CH₂CH₂OH; or R4 and R5 form an N-containing five- or six-memberedring or heteroaromatic ring selected from the group consisting of animidazole ring and a piperidine ring.
 3. A compound according to claim 2where X is S.
 4. A compound according to claim 2 where X is NH.
 5. Acompound according to claim 3, which is1-[4-(2-dimethylaminoethylsulfanyl)phenyl]-1,2-diphenyl-4-chloro-but-1-ene;or a stereoisomer; or a non-toxic pharmaceutically acceptable saltthereof.
 6. A compound according to claim 4, which isN-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenyl]-N′,N′-dimethylethane-1,2-diamine;or a stereoisomer; or a non-toxic pharmaceutically acceptable saltthereof.
 7. A compound according to claim 1, wherein R1 is H, halogen,OCH₃, or OH; and R2 is —Y—(CH₂)_(n)CH₂—O—R6 where Y is O, NH or S and nis an integer from 1 to 4; and R6 is H, —CH₂CH₂OH, or —CH₂CH₂Cl.
 8. Acompound according to claim 7 where Y is O.
 9. A compound according toclaim 7 where Y is S.
 10. A compound according to claim 7 where Y is NH.11. A compound according to claim 8, which is selected from the groupconsisting of2-{4-[4-chloro-2-phenyl-1-(4-fluorophenyl)but-1-enyl]phenoxy}ethanol,2-{4-[4-chloro-2-phenyl-1-(4-chlorophenyl)but-1-enyl]phenoxy}ethanol,3-{4-chloro-1-[4-(2-hydroxyethoxy)phenyl]-2-phenyl-but-1-enyl}-phenol,4-{1-(2-chloroethyl)-2-[4-(2-hydroxyethoxy)phenyl]-2-phenylvinyl}phenol,2-{4-[4-chloro-1,2-bis(4-chlorophenyl)but-1-enyl]phenoxy}ethanol,2-{4-[4-chloro-2-(4-chlorophenyl)-1-(4-methoxyphenyl)but-1-enyl]phenoxy}ethanol,2-[3-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol,3-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]propan-1-ol,2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol,3-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxymethyl]pentan-3-ol,1-(4-{2-[(2-chloroethoxy]ethoxy}phenyl)-4-chloro-1-(4-chlorophenyl)-2-phenyl-but-1-eneand 1-(4-{2-[(2-chloroethoxy]ethoxy}phenyl)4-chloro-1-(4-fluorophenyl)-2-phenyl-but-1-ene; or astereoisomer; or a non-toxic pharmaceutically acceptable salt thereof.12. A compound according to claim 9, which is2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)-phenylsulfanyl]ethanol; or astereoisomer; or a non-toxic pharmaceutically acceptable salt thereof.13. A compound according to claim 10, which is2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenylamino]ethanol; or astereoisomer; or a non-toxic pharmaceutically acceptable salt thereof.14. A compound according to claim 1, which is selected from the groupconsisting of3-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxymethyl]pentan-3-ol,2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]butan-1-ol,3-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]propane-1,2-diol,3-{4-[4-chloro-1-(4-chlorophenyl)-2-phenyl-but-1-enyl]phenoxy}propane-1,2-diol,4-chloro-1-[4-(2-methylsulfanyl-ethoxy)phenyl]-1,2-diphenyl-but-1-ene,4-chloro-1-[4-(2-chloroethoxy)phenyl]-1,2-bis(4-chlorophenyl)-but-1-ene,and {4-[4-chloro-1-(4-chlorophenyl)-2-phenylbut-1-enyl]phenoxy}aceticacid; or a stereoisomer; or a non-toxic pharmaceutically acceptable saltor ester thereof.
 15. A compound according to claim 1, which is3-(4-chloro-1-{4-[2-(2-hydroxyethoxy)ethoxy]phenyl}-2-phenylbut-1-enyl)phenol;or a stereoisomer; or a non-toxic pharmaceutically acceptable saltthereof.
 16. A pharmaceutical composition comprising an amount effectiveto produce a tissue specific estrogenic and/or antiestrogenic effect ofsaid selective estrogen receptor modulator compound according to claim1, or a stereoisomer, or a non-toxic pharmaceutically acceptable salt orester thereof, and a pharmaceutically compatible acceptable carriertherefor.
 17. A method of producing a tissue specific estrogenic and/orantiestrogenic effect in a subject in which such an effect is desiredwhich comprises administering to said subject said selective estrogenreceptor modulator compound according to claim 1, or a stereoisomer, ora non-toxic pharmaceutically acceptable salt or ester thereof in anamount sufficient to produce the desired effect.
 18. A compoundaccording to claim 1, wherein R1 is H, halogen, OCH₃, or OH; and R2 is—Y—(CH₂)_(n)CH₂—O—R6 where Y is O, NH or S and n is an integer from 1 to4; and R6 is —CH₂CH₂OH.
 19. A compound according to claim 1, wherein R1is H, halogen, OCH₃, or OH; and R2 is —Y—(CH₂)_(n)CH₂—O—R6 where Y is NHor S and n is an integer from 1 to 4; and R6 is H, —CH₂CH₂OH, or—CH₂CH₂Cl.
 20. A compound according to claim 1, wherein R1 is H,halogen, OCH₃, or OH; and R2 is 2,3-dihydroxypropoxy,2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy,2,2-diethyl-2-hydroxyethoxy, or carboxymethoxy.